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Фармакогеномика (подходы к индивидуализации медикаментозной терапии)

Журнальные статьи

1. Ahn K. et al. Functional mapping of drug response with pharmacodynamic-pharmacokinetic principles // Trends Pharmacol. Sci. 2010. Vol. 31, № 7. P. 306–311.

Recent research in pharmacogenomics has inspired our hope to predict drug response by linking it with DNA information extracted from the human genome. However, many genetic models of drug response do not incorporate biochemical principles of host-drug interactions, limiting the effectiveness of the predictive models. We argue that functional mapping, a computational tool aimed at identifying genes and genetic networks that control dynamic traits, can help explain the detailed genetic architecture of drug response by incorporating pharmacokinetic and pharmacodynamic processes. Functional mapping is particularly powerful in determining the genetic commonality and differences of drug efficacy vs. drug toxicity and drug sensitivity vs. drug resistance. We pinpoint several future directions in which functional mapping can be coupled with systems biology to unravel the genetic and metabolic machinery of drug response.


2. Alomar M.J. Factors affecting the development of adverse drug reactions (Review article) // Saudi Pharm. J. 2014. Vol. 22, № 2. P. 83–94.

Objectives: To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources: A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary: Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion: Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection.


3. Anwar M.A. et al. Glucocorticoid-induced fetal origins of adult hypertension: Association with epigenetic events // Vasc. Pharmacol. 2016. Vol. 82. P. 41–50.

Hypertension is a predominant risk factor for cardiovascular diseases and a major health care burden. Accumulating epidemiological and experimental evidence suggest that adult-onset hypertension may have its origins during early development. Upon exposure to glucocorticoids, the fetus develops hypertension, and the offspring may be programmed to continue the hypertensive trajectory into adulthood. Elevated oxidative stress and deranged nitric oxide system are not only hallmarks of adult hypertension but are also observed earlier in life. Endothelial dysfunction and remodeling of the vasculature, which are robustly associated with increased incidence of hypertension, are likely to have been pre-programmed during fetal life. Apparently, genomic, non-genomic, and epigenomic factors play a significant role in the development of hypertension, including glucocorticoid-driven effects on blood pressure. In this review, we discuss the involvement of the aforementioned participants in the pathophysiology of hypertension and suggest therapeutic opportunities for targeting epigenome modifiers, potentially for personalized medicine.


4. Arnett D.K., Claas S.A., Glasser S.P. Pharmacogenetics of antihypertensive treatment // Vasc. Pharmacol. 2006. Vol. 44, № 2. P. 107–118.

Hypertension is a common disorder associated with increased cardiovascular morbidity and mortality. Unfortunately, in the US only about one-third of those who are aware of their hypertensive status have their blood pressure adequately controlled. One reason for this is the variable and unpredictable response individuals have to pharmacologic treatment. Clinicians often resort to "trial-and-error" to match patients with effective drug treatment. Hypertension pharmacogenetics seeks to find genetic predictors of drug response. To date, more than forty studies have investigated associations between genetic polymorphisms and response to antihypertensive drugs. Angiotensin-converting enzyme inhibitors and beta blockers have been most frequently studied, followed by angiotensin II blockers, diuretics, adrenergic alpha-agonists, and calcium channel blockers. Renin-angiotensin-aldosterone system genes have been the most widely studied, with the angiotensin-converting enzyme I/D variant being typed in about one-half of all hypertension pharmacogenetic studies. In total, 160 possible gene polymorphism-drug interactions have been explored, with about one-quarter of these showing that genes predict drug response. However. disparate and conflicting findings have been the rule rather than the exception, and the discovery of clinically relevant antihypertensive drug-response genes remains elusive. While there is a growing enthusiasm that pharmacogenetics of hypertension is important.. the translation of pharmacogenetic findings to clinical practice in the future will depend on additional studies to enhance our pharmacogenetics knowledge base, the availability of pharmacogenetic screening tests that are affordable and easy to implement in clinical practice, a cohort of clinicians who are trained to interpret genetic test results, and health care systems that pay for them. Caution regarding the future of hypertension pharmacogenetics is warranted.


5. Azuma J., Nonen S. Chronic heart failure: beta-blockers and pharmacogenetics // Eur. J. Clin. Pharmacol. 2009. Vol. 65, № 1. P. 3–17.

The European Society of Cardiology recommends that beta-blockers should be considered for treating all patients with stable, mild, moderate, or severe heart failure (HF) who are receiving standard treatment, unless there is a contraindication. Despite the significant benefit of the drug, there is widespread recognition of patient-to-patient variability in drug response. The genetic determinants of responses to drugs have important implications for the clinical course and management of HF. Pharmacogenetics (PGt) has drawn great attention for its potential to redirect personal care and public health paradigms. The aim of this review was to gather information on PGt of beta-blockers in HF treatment. We searched for articles related to PGt of beta-blockers in the PubMed database and attempted to cover all related articles. Several genetic polymorphisms affecting proteins in the beta-adrenergic receptor signaling pathway have been proposed as modifiers of HF risk. The most relevant of these to this review is the pharmacogenetic interactions between the genetic variants of catecholamine receptors or their effectors and beta-blockade for the treatment of HF. Interindividual variability of responsiveness to beta-blockers can be explained by PGt data of adrenaline-related genes. To demonstrate that pharmacogenetic intervention produces successful individualized beta-blocker treatment for HF patients, prospective, randomized, and pharmacogenomics (PGx)-based clinical trials are required. Our assessment is that we are already at a turning point in the history of clinical pharmacology.


6. Bartlett M.J., Shephard E.A. The integration and interpretation of pharmacogenomics – a comparative study between the United States of America and Europe: towards better health care // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 2. P. 91–96.

The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe. The article discusses also how interpretation of pharmacogenomics could move forward to better implementation in health care.


7. Baye T.M., Wilke R.A. Mapping genes that predict treatment outcome in admixed populations // Pharmacogenomics J. 2010. Vol. 10, № 6. P. 465–477.

There is great interest in characterizing the genetic architecture underlying drug response. For many drugs, gene-based dosing models explain a considerable amount of the overall variation in treatment outcome. As such, prescription drug labels are increasingly being modified to contain pharmacogenetic information. Genetic data must, however, be interpreted within the context of relevant clinical covariates. Even the most predictive models improve with the addition of data related to biogeographical ancestry. The current review explores analytical strategies that leverage population structure to more fully characterize genetic determinants of outcome in large clinical practice-based cohorts. The success of this approach will depend upon several key factors: (1) the availability of outcome data from groups of admixed individuals (that is, populations recombined over multiple generations), (2) a measurable difference in treatment outcome (that is, efficacy and toxicity end points), and (3) a measurable difference in allele frequency between the ancestral populations.


8. Behrooz A. Pharmacogenetics and anaesthetic drugs: Implications for perioperative practice // Ann. Med. Surg. 2015. Vol. 4, № 4. P. 470–474.

Pharmacogenetics seeks to elucidate the variations in individual's genetic sequences in order to better understand the differences seen in pharmacokinetics, drug metabolism, and efficacy between patients. This area of research is rapidly accelerating, aided by the use of novel and more economical molecular technologies. A substantial evidence base is being generated with the hopes that in the future it may be used to generate personalised treatment regimens in order to improve patient comfort and safety and reduce incidences of morbidity and mortality. Anaesthetics is an area of particular interest in this field, with previous research leading to better informed practice, specifically with regards to pseudocholinesterase deficiency and malignant hyperthermia. In this review, recent pharmacogenetic data pertaining to anaesthetic drugs will be presented and possible future applications and implications for practice will be discussed.


9. Beitelshees A.L., McLeod H.L. Applying pharmacogenomics to enhance the use of biomarkers for drug effect and drug safety // Trends Pharmacol. Sci. 2006. Vol. 27, № 9. P. 498–502.

Pharmacogenomics is used to improve patient outcome by maximizing the likelihood of desired effects and minimizing the risk of adverse events using an individual's genetic profile. As such, pharmacogenomics can be used to improve current risk-management strategies (improving the risk-benefit balance). Two areas of great promise for pharmacogenomics in this regard are emerging: (i) the pharmacogenomics of modulating disease biomarkers (to provide insight into novel mechanisms of drug response and to identify the patients most likely to respond to a drug in a favorable way); and (ii) using pharmacogenomics to enhance drug safety. Given that novel biomarkers could enable the earlier detection of many diseases and more-widespread therapies for primary prevention, pharmacogenomics provides the opportunity to identify the patients most likely to respond to these therapies, thereby preserving valuable health-care resources. The use of pharmacogenomics in pharmacovigilance could also be useful for risk-stratifying patients and for helping to identify the mechanisms involved in adverse events.


10. Brandsch M., Knuetter I., Bosse-Doenecke E. Pharmaceutical and pharmacological importance of peptide transporters // J. Pharm. Pharmacol. 2008. Vol. 60, № 5. P. 543–585.

Peptide transport is currently a prominent topic in membrane research. The transport proteins involved are under intense investigation because of their physiological importance in protein absorption and also because peptide transporters are possible vehicles for drug delivery. Moreover, in many tissues peptide carriers transduce peptidic signals across membranes that are relevant in information processing. The focus of this review is on the pharmaceutical relevance of the human peptide transporters PEPT1 and PEPT2. In addition to their physiological substrates, both carriers transport many beta-lactam antibiotics, valaciclovir and other drugs and prodrugs because of their sterical resemblance to di- and tripeptides. The primary structure, tissue distribution and substrate specificity of PEPT1 and PEPT2 have been well characterized. However, there is a dearth of knowledge on the substrate binding sites and the three-dimensional structure of these proteins. Until this pivotal information becomes available by X-ray crystallography, the development of new drug substrates relies on classical transport studies combined with molecular modelling. In more than thirty years of research, data on the interaction of well over 700 di- and tripeptides, amino acid and peptide derivatives, drugs and prodrugs with peptide transporters have been gathered. The aim of this review is to put the reports on peptide transporter-mediated drug uptake into perspective. We also review the current knowledge on pharmacogenomics and clinical relevance of human peptide transporters. Finally, the reader's attention is drawn to other known or proposed human peptide-transporting proteins.


11. Bristow M.R. Pharmacogenetic targeting of drugs for heart failure // Pharmacol. Ther. 2012. Vol. 134, № 1. P. 107–115.

Pharmacogenetic drug development represents an ideal approach to enhance a drug's response rate in a disease indication cohort, thereby increasing the therapeutic index. The most straightforward way to develop a pharmacogenetically targeted drug is to identify a functionally important genetic variant in the drug's target(s), or in a target modifier. There are two general ways to detect such genetic variation, the candidate gene variant hypothesis testing approach, and genome wide scanning "hypothesis free" methods. In order to impact drug development either approach needs to be implemented early in the drug development process, with the candidate strategy having the advantage that it can be introduced earlier, during preclinical development. Contrary to conventional wisdom, a pharmacogenetic approach does not increase the overall efficiency of drug development, because the required additional genetic and biologic function discovery work will be layered onto standard regulatory steps. However, identification of a hyper-responsive subpopulation by a genetic biomarker does increase the chance of success in Phase 3, which may lower the cost of pivotal trials. Perhaps most importantly from a commercial standpoint, pharmacogenetics use patents, typically submitted relatively late in the development process, can greatly extend a drug's exclusivity period. This will recoup the extra cost inherent to pharmacogenetic drug development, and increase the product's return on investment by providing a longer period for branded exclusivity. Most importantly, pharmacogenetic targeting will result in a therapeutic agent with a greater therapeutic index and a better pharmacoeconomic profile than would be possible with pangenetic, entire cohort positioning.


12. Bromley C.M. et al. Designing pharmacogenetic projects in industry: practical design perspectives from the Industry Pharmacogenomics Working Group // Pharmacogenomics J. 2009. Vol. 9, № 1. P. 14–22.

Pharmacogenetic association studies have the potential to identify variations in DNA sequence which impact drug response. Identifying these DNA variants can help to explain interindividual variability in drug response; this is the first step in personalizing dosing and treatment regimes to a patient's needs. There are many intricacies in the design and analysis of pharmacogenetic association studies, including having adequate power, selecting proper endpoints, detecting and correcting the effects of population stratification, modeling genetic and nongenetic covariates accurately, and validating the results. At this point there are no formal guidelines on the design and analysis of pharmacogenetic studies. The Industry Pharmacogenomics Working Group has initiated discussions regarding potential guidelines for pharmacogenetic study design and analyses (http://i-pwg.org) and the results from these discussions are presented in this paper.


13. Brosen K. Pharmacogenetics of drug oxidation via cytochrome P450 (CYP) in the populations of Denmark, Faroe Islands and Greenland // Drug Metabolism and Personalized Therapy. 2015. Vol. 30, № 3. P. 147–163.

Denmark, the Faroe Islands and Greenland are three population-wise small countries on the northern part of the Northern Hemisphere, and studies carried out here on the genetic control over drug metabolism via cytochrome P450 have led to several important discoveries. Thus, CYP2D6 catalyzes the 2-hydroxylation, and CYP2C19 in part catalyzes the N-demethylation of imipramine. The phenomenon of phenocopy with regard to CYP2D6 was first described when Danish patients changed phenotype from extensive to poor metabolizers during treatment with quinidine. It was a Danish extensive metabolizer patient that became a poor metabolizer during paroxetine treatment, and this was due to the potent inhibition of CYP2D6 by paroxetine, which is also is metabolized by this enzyme. Fluoxetine and norfluoxetine are also potent inhibitors of CYP2D6, and fluvoxamine is a potent inhibitor of both CYP1A2 and CYP2C19. The bioactivation of proguanil to cycloguanil is impaired in CYP2C19 poor metabolizers. The O-demethylation of codeine and tramadol to their respective my-opioid active metabolites, morphine and (+)-O-desmethyltramadol was markedly impaired in CYP2D6 poor metabolizers compared to extensive metabolizers, and this impairs the hypoalgesic effect of the two drugs in the poor metabolizers. The frequency of CYP2D6 poor metabolizers is 2%–3% in Greenlanders and nearly 15% in the Faroese population. The frequency of CYP2C19 poor metabolizers in East Greenlanders is approximately 10%. A study in Danish mono and dizygotic twins showed that the non-polymorphic 3-N-demethylation of caffeine catalyzed by CYP1A2 is subject to approximately 70% genetic control.


14. Cacabelos R. Epigenomic Networking in Drug Development: From Pathogenic Mechanisms to Pharmacogenomics // Drug Dev. Res. 2014. Vol. 75, № 6. P. 348–365.

Different epigenetic alterations (DNA methylation, histone modifications, chromatin remodeling, noncoding RNA dysregulation) are associated with the phenotypic expression of complex disorders in which genomic, epigenomic, proteomic, and metabolomic changes, in conjunction with environmental factors, are involved. As epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions, a series of epigenetic drugs have been developed, including DNA methyltransferase inhibitors (nucleoside analogs, small molecules, bioproducts, antisense oligonucleotides, miRNAs), histone deacetylase inhibitors (short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, ketones, sirtuin inhibitors, sirtuin activators), histone acetyltransferase modulators, histone methyltransferase inhibitors, histone demethylase inhibitors, and noncoding RNAs (miRNAs), with potential effects against myelodysplastic syndromes, different types of cancer, and neurodegenerative disorders. Pharmacogenetic and pharmacoepigenetic studies are required for the proper evaluation of efficacy and safety issues in clinical trials with epigenetic drugs.


15. Cacabelos R., Martinez-Bouza R. Genomics and Pharmacogenomics of Dementia // CNS Neurosci. Ther. 2011. Vol. 17, № 5. P. 566–576.

Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1xN/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.


16. Cacabelos R., Martinez-Bouza R. Genomics and Pharmacogenomics of Schizophrenia // CNS Neurosci. Ther. 2011. Vol. 17, № 5. P. 541–565.

Schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation. SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes. Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system (CNS) disorders.


17. Carr D.F. et al. Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review // Pharmacogenomics J. 2009. Vol. 9, № 5. P. 291–305.

Genetic polymorphisms in the one-carbon folate pathway have been widely studied in association with a number of conditions. Most of the research has focused on the 677C>T polymorphism in the coding region of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene. However, there are a total of 25 genes in this pathway coding for enzymes, transporters and receptors, which can be investigated using 267 tagging single nucleotide polymorphisms (SNPs); using SNP database (dbSNP), 38 non-synonymous SNPs with a minor allele frequency of >5% are present in these genes. Most of these variants have not been investigated in relation to disease or drug response phenotypes. In addition, their functional consequences are largely unknown. Prediction of the functional effect using six publicly available programs (PolyPhen, SIFT BLink, PMut, SNPs3D, I-Mutant2.0 and LS-SNP) was limited to functionally well-characterized SNPs such as MTHFR c. 677C>T and c. 1298A>C ranking low. Epigenetic modifications may also be important with some of these genes. In summary, to date, investigation of the one-carbon folate pathway genes has been limited. Future studies should aim for a more comprehensive assessment of this pathway, while further research is also required in determining the functional effects of these genetic variants.


18. Carr D.F., Alfirevic A., Pirmohamed M. Pharmacogenomics: Current State-of-the-Art // Genes. 2014. Vol. 5, № 2. P. 430–443.

The completion of the human genome project 10 years ago was met with great optimism for improving drug therapy through personalized medicine approaches, with the anticipation that an era of genotype-guided patient prescribing was imminent. To some extent this has come to pass and a number of key pharmacogenomics markers of inter-individual drug response, for both safety and efficacy, have been identified and subsequently been adopted in clinical practice as pre-treatment genetic tests. However, the universal application of genetics in treatment guidance is still a long way off. This review will highlight important pharmacogenomic discoveries which have been facilitated by the human genome project and other milestone projects such as the International HapMap and 1000 genomes, and by the continued development of genotyping and sequencing technologies, including rapid point of care pre-treatment genetic testing. However, there are still many challenges to implementation for the many other reported biomarkers which continue to languish within the discovery phase. As technology advances over the next 10 years, and the costs fall, the field will see larger genetic data sets, including affordable whole genome sequences, which will, it is hoped, improve patient outcomes through better diagnostic, prognostic and predictive biomarkers.


19. Cavallari L.H., Shin J., Perera M.A. Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants // Pharmacotherapy. 2011. Vol. 31, № 12. P. 1192–1207.

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (GYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of thee genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration-cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available.


20. Cespedes-Garro C. et al. Pharmacogenetics in Central American healthy volunteers: interethnic variability // Drug Metabolism and Personalized Therapy. 2014. Vol. 30, № 1. P. 19–31.

Ethnicity is one of the major factors involved in interindividual variability to drug response. This study aims to describe the frequency of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in Central American healthy volunteers and to determine its interethnic variability. Twenty-six original research articles on allelic, genotypes or metabolic phenotype frequencies were analyzed, in which a total number of 7611 Central American healthy volunteers were included (6118 were analyzed for genotype and 1799 for metabolic phenotype). No reports were available for population from Belize and Honduras. The CYP2D6*4 and *5 frequencies in Amerindian populations from Costa Rica have shown to be among the highest frequencies so far reported in the world. Furthermore, NAT2*5 and *6 presented higher frequencies in admixed populations than in Amerindians, but, inversely, the NAT2*7 was more frequent in Amerindians compared to an admixed population. Likewise, different patterns of distribution have been shown in HLA-A*02, *03 and HLA-B*07 among Native populations from Latin America. Reports on Central American populations were also found for the CYP2C19, LDLR, CYP2E1, MDR1, G6PD, TP53, CYP1A2, CYP3A4 and CYP3A5 biomarkers, but no data were available for the other 91 pharmacogenetic biomarkers revised in Central American populations. Differences in the frequency of some pharmacogenetic biomarkers and metabolic phenotypes were found, showing interethnic variability within Central American and with other Latin American populations.


21. Chiurillo M.A. Genomic biomarkers related to drug response in Venezuelan populations // Drug Metabolism and Personalized Therapy. 2014. Vol. 30, № 1. P. 33–41.

Pharmacogenetics is being applied to develop individual specific therapies considering different ethnic groups and mixed populations. The Venezuelan population is very heterogeneous as a result of the admixture process that occurred between Native Americans, Europeans, and Africans through five centuries. This review provides a summary of the literature concerning gene variants within drug-metabolizing enzymes, drug targets, and drug receptors (CYP2C19, CYP2D6, GSTM1, GSTT1, GSTP1, NAT2, MTHFR, LEP, LEPR, LTC4S, and ADR?2 genes) evaluated in the Venezuelan population. In particular, most of the studies were conducted with relatively low numbers of individuals. Some of these studies included analyses of genetic polymorphisms in native groups living in this country. Although the recent studies represent a hopeful progress toward the inclusion of the Venezuelan population among those who will benefit from the implementation of pharmacogenetic principles and tools in drug therapy, there are not yet sufficient data concerning allelic frequencies of genomic biomarkers related to drug response for their implementation in clinical practice. Therefore, there is a critical need for more research in pharmacogenetics in Venezuela to increase data availability.


22. Claudio-Campos K. et al. Pharmacogenetics of drug-metabolizing enzymes in US Hispanics // Drug Metabolism and Personalized Therapy. 2014. Vol. 30, № 2. P. 87–105.

Although the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes. CYP3A5*3 (0.245–0.867) showed the largest frequency in a US Hispanic population. A higher prevalence of CYP2C9*3, CYP2C19*4, and UGT2B7 IVS1+985 A>G was observed in US Hispanic vs. non-Hispanic populations. We found interethnic and intraethnic variability in frequencies of genetic polymorphisms for metabolizing enzymes, which highlights the need to define the ancestries of participants in pharmacogenetic studies. New approaches should be integrated in experimental designs to gain knowledge about the clinical relevance of the unique combination of genetic variants occurring in this admixed population. Ethnic subgroups in the US Hispanic population may harbor variants that might be part of multiple causative loci or in linkage-disequilibrium with functional variants. Pharmacogenetic studies in Hispanics should not be limited to ascertain commonly studied polymorphisms that were originally identified in their parental populations. The success of the Personalized Medicine paradigm will depend on recognizing genetic diversity between and within US Hispanics and the uniqueness of their genetic backgrounds.


23. Claudio-Campos K. et al. Pharmacogenetics of healthy volunteers in Puerto Rico // Drug Metabolism and Personalized Therapy. 2015. Vol. 30, № 4. P. 239–249.

Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island.


24. Close S.L. Pharmacogenetics and pharmacogenomics of thienopyridines: clinically relevant? // Fundam. Clin. Pharmacol. 2012. Vol. 26, № 1. P. 19–26.

Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines.


25. Crea F. et al. Pharmacogenomics and cancer stem cells: a changing landscape? // Trends Pharmacol. Sci. 2011. Vol. 32, № 8. P. 487–494.

Pharmacogenomics in oncology holds the promise to personalize cancer therapy. However, its clinical application is still limited to a few genes, and, in the large majority of cancers, the correlation between genotype and clinical outcome has been disappointing. One possible explanation is that current pharmacogenomic studies do not take into account the emerging role of cancer stem cells (CSCs) in drug sensitivity and resistance. CSCs are a subpopulation of cells driven by specific signal-transduction pathways, but genetic variants affecting their activity are generally neglected in current pharmacogenomic studies. Moreover, in several malignancies, CSCs represent a rare sub-population; therefore, whole tumor profiling might mask CSC gene expression patterns. This article reviews current evidence on CSC chemoresistance and shows how common genetic variations in CSC-related genes may predict individual response to anti-cancer agents. Furthermore, we provide insights into the design of pharmacogenomic studies to address the clinical usefulness of CSC genetic profiling.


26. D’Alessandro A., Zolla L. Pharmacoproteomics: a chess game on a protein field // Drug Discov. Today. 2010. Vol. 15, № 23–24. P. 1015–1023.

The application of proteomics in the field of drug discovery development and the assessment of drug administration is known as pharmacoproteomics. As a branch of proteomics - perhaps the most promising and rapidly evolving field of the post-genomic era - pharmacoproteomics has inherited all the promises that pharmacogenomics has hitherto left unfulfilled. On the road to tailor-made drugs, whole protein profiles of healthy individuals have been progressively expanded, either qualitatively or quantitatively. In this review article, we provide general information about technical advancements in the field of proteomics (the pieces of this intriguing chess game) and show how this progress has furthered our understanding of biological systems. Pitfalls on the field of biomarker individuation and drug discovery and/or testing are also discussed.


27. Daly A.K. Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations // Drug Metabolism and Personalized Therapy. 2015. Vol. 30, № 3. P. 165–174.

Data on frequency of pharmacogenetic polymorphisms in the UK population are limited. However, availability of whole genome sequencing data on 94 UK controls of European ethnicity from the 1000 genomes project together with similar data on other populations provides a valuable new source of data in this area and allows direct comparison of allele frequencies with those for other European populations. The ethnic diversity of the UK population also needs to be considered, and 1000 genomes includes data on South Asians, the most common ethnic group in the UK after White Europeans. Allele frequencies for polymorphisms in genes relevant to phase I and phase II drug metabolism for UK, Finnish, Spanish and South Asian populations were obtained from the literature and 1000 genomes. Generally there was good agreement between the literature and 1000 genomes reports. CYP2D6*4, the most common CYP2D6 poor metabolizer allele among Europeans, appears more common in the UK than in Spain and Finland, whereas, as suggested previously, CYP2C19*2 and CYP2C9*2 appear more common in Finland and Spain, respectively, than in the UK. South Asians show low frequencies of CYP2C9*2 and CYP2C19*17 but higher frequencies of CYP2C19*2 compared with UK residents of European ethnicity. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs.


28. de Leon J. Pharmacogenomics: The Promise of Personalized Medicine for CNS Disorders // Neuropsychopharmacology. 2009. Vol. 34, № 1. P. 159–172.

This review focuses first on the concept of pharmacogenomics and its related concepts biomarkers and personalized prescription). Next, the first generation of five DNA pharmacogenomic tests used in the clinical practice of psychiatry is briefly reviewed. Then the possible involvement of these pharmacogenomic tests in the exploration of early clinical proof of mechanism is described by using two of the tests and one example from the pharmaceutical industry iloperidone clinical trials). The initial attempts to use other microarray tests measuring RNA expression) as peripheral biomarkers for CNS disorders are briefly described. Then the challenge of taking pharmacogenomic tests compared to drugs) into clinical practice is explained by focusing on regulatory oversight, the methodological/scientific issues concerning diagnostic tests, and cost-effectiveness issues. Current information on medicine-based evidence and cost-effectiveness usually focuses on average patients and not the outliers who are most likely to benefit from personalized prescription. Finally, future research directions are suggested. The future of 'personalized prescription' in psychiatry requires consideration of pharmacogenomic testing and environmental and personal variables that influence pharmacokinetic and pharmacodynamic drug response for each individual drug used by each patient.


29. Dorn G.W., Liggett S.B. Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure // Mol. Pharmacol. 2009. Vol. 76, № 3. P. 466–480.

One of the goals of pharmacogenomics is the use of genetic variants to predict an individual's response to treatment. Although numerous candidate and genome-wide associations have been made for cardiovascular response-outcomes, little is known about how a given polymorphism imposes the phenotype. Such mechanisms are important, because they tie the observed human response to specific signaling alterations and thus provide cause-and-effect relationships, aid in the design of hypothesis-based clinical studies, can help to devise work-around drugs, and can reveal new aspects of the pathophysiology of the disease. Here we discuss polymorphisms within the adrenergic receptor network in the context of heart failure and beta-adrenergic receptor blocker therapy, where multiple approaches to understand the mechanism have been undertaken. We propose a comprehensive series of studies, ranging from transfected cells, transgenic mice, and ex vivo and in vitro human studies as a model approach to explore mechanisms of action of pharmacogenomic effects and extend the field beyond observational associations.


30. Dotson W.D. et al. Prioritizing Genomic Applications for Action by Level of Evidence: A Horizon-Scanning Method // Clin. Pharmacol. Ther. 2014. Vol. 95, № 4. P. 394–402.

As evidence accumulates on the use of genomic tests and other health-related applications of genomic technologies, decision makers may increasingly seek support in identifying which applications have sufficiently robust evidence to suggest they might be considered for action. As an interim working process to provide such support, we developed a horizon-scanning method that assigns genomic applications to tiers defined by availability of synthesized evidence. We illustrate an application of the method to pharmacogenomics tests.


31. Drozda K., Mueller D.J., Bishop J.R. Pharmacogenomic Testing for Neuropsychiatric Drugs: Current Status of Drug Labeling, Guidelines for Using Genetic Information, and Test Options // Pharmacotherapy. 2014. Vol. 34, № 2. P. 166–184.

Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to guide pharmacotherapy used to treat psychiatric and neurological (neuropsychiatric) conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of existing genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for determining the starting and target doses, as well as drug interaction potential, for a number of other drugs. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.


32. Eberly A.L. et al. Optimal Prevention of Seizures Induced by High-Dose Busulfan // Pharmacotherapy. 2008. Vol. 28, № 12. P. 1502–1510.

High-dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-ctonic in character. Phenytoin has been the preferred drug to treat busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. it is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early, data of its efficacy are promising, although further study is needed.


33. Evans B.J. Distinguishing product and practice regulation in personalized medicine // Clin. Pharmacol. Ther. 2007. Vol. 81, № 2. P. 288–293.

Protecting the public from faulty targeting of medicines, while preserving the crucial distinction between product and practice regulation, may require innovative regulatory approaches and close, ongoing involvement by the medical profession. This article explores four problem areas: validation of clinical claims for tests used in targeting therapies; developing and implementing appropriate restrictions on off-label use; promoting consistent concepts of clinical utility for use in various regulatory, reimbursement, and judicial contexts; and communication of clear information to guide clinicians in appropriate use of targeted therapeutic products. The article suggests an approach for addressing these problems by sharing regulatory activities between the Food and Drug Administration and a newly-created clinical standards board formed within the medical and scientific communities.


34. Falvella F.S. et al. Pharmacogenetics-based optimisation of atazanavir treatment: potential role of new genetic predictors // Drug Metabolism and Personalized Therapy. 2017. Vol. 32, № 2. P. 115–117.

"In conclusion, our data confirm the association between UGT1A1*28 allele and the risk of hyperbilirubinemia, suggesting that the PPARA rs4253728 variant allele may be an additional genetic predictor of higher serum bilirubin. Finally, an increased risk of supra-therapeutic ATV concentrations in poor CYP3A metabolisers may be suggested. However, this observation, which is useful for the personalisation of drug treatment, must be confirmed in a large series of patients receiving an ATV/r-based treatment."


35. Fang H. et al. FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science // Drug Discov. Today. 2016. Vol. 21, № 10. P. 1566–1570.

Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through this data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80 000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.


36. Fleeman N. et al. Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses // Pharmacogenomics J. 2011. Vol. 11, № 1. P. 1–14.

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.


37. Franconi F., Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women // Br. J. Pharmacol. 2014. Vol. 171, № 3. P. 580–594.

Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.


38. Fricke-Galindo I. et al. Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics) // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 2. P. 61–81.

Mexico presents a complex population diversity integrated by Mexican indigenous (MI) (7% of Mexico’s population) and Mexican mestizos (MMs). This composition highlights the importance of pharmacogenetic studies in Mexican populations. The aims of this study were to analyze the reported frequencies of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in healthy volunteers from Mexican populations and to assess its interethnic variability across MI and MM populations. After a literature search in PubMed, and according to previously defined inclusion criteria, 63 pharmacogenetic studies performed in Mexican healthy volunteers up to date were selected. These reports comprised 56,292 healthy volunteers (71.58% MM). Allele frequencies in 31 pharmacogenetic biomarkers, from 121 searched, are described. Nine of these biomarkers presented variation within MM and MI groups. The frequencies of CYP2D6*3, *4, *5, *10, *17, *35 and *41 alleles in the MM group were different from those reported in the MI group. CYP2C9*2 and *3 alleles were more frequent in MM than in MI populations (?2 test, p<0.05). CYP2C19*3 allele was not found in the MM or MI populations reported. For UGT1A1*28, only one study was found. HLA-A*31:01 and HLA-B*15:02 were present in some MM and MI populations. Poor metabolizers for CYP2D6 and CYP2C9 were more frequent in MM than in MI groups (?2 test, p<0.05). Only 26% of the relevant pharmacogenetic biomarkers searched have been studied in Mexican healthy volunteers; therefore, further studies are warranted. The frequency variation of biomarkers in MM and MI populations could be important for the clinical implementation of pharmacogenetics in Mexico.


39. Gelissen I.C., McLachlan A.J. The pharmacogenomics of statins // Pharmacol. Res. 2014. Vol. 88. P. 99–106.

The statin class of cholesterol-lowering drugs have been used for decades to successfully lower plasma cholesterol concentrations and cardiovascular risk. Adverse effects of statins are generally considered mild, but increase with age of patients and polypharmacy. One aspect of statin therapy that is still difficult for prescribers to predict is the individual's response to statin therapy. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect statin efficacy and safety. In this review, a number of candidates that affect statin pharmacokinetics and pharmacodynamics are discussed. Some of these candidates, in particular those involved in import and efflux of statins, have now been linked to increased risk of side effects. Furthermore, pharmacogenomic studies continue to reveal new players that are involved in the fine-tuning of the complex regulation of cholesterol homeostasis and response to statins.


40. Giacomini K.M. et al. The Pharmacogenetics Research Network: From SNP discovery to clinical drug response // Clin. Pharmacol. Ther. 2007. Vol. 81, № 3. P. 328–345.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase 11 drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.


41. Gibson S., Raziee H.R., Lemmens T. Why the Shift? Taking a Closer Look at the Growing Interest in Niche Markets and Personalized Medicine // World Med. Health Policy. 2015. Vol. 7, № 1. P. 3–27.

Pharmaceutical research and development is increasingly focused on niche markets, most notably treatments for rare diseases and "personalized" medicine. Drawing on the results of a qualitative study of 34 key Canadian stakeholders (including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates), we explore the major trends that are reportedly contributing to the growing interest of the pharmaceutical industry in niche markets. Informed by both these key informant interviews and a review of the relevant literature, our paper provides a critical analysis of the many different-and sometimes conflicting-views on the reasons for and extent of the shift toward niche markets. We consider some of the potential advantages to industry, as well the important implications and risks that arise from the increasing pursuit of niche markets and pharmacogenomics. While there are many potential benefits associated with targeted therapies and drug development for historically neglected rare diseases, niche market therapies also present evidentiary challenges (e.g., smaller clinical trials and enrichment strategies) that can make approval decisions difficult, and uncertainties remain around the true benefits of many therapies.


42. Godman B. et al. Personalizing health care: feasibility and future implications // BMC Med. 2013. Vol. 11. P. 179.

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer's perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.


43. Guillemette C., Levesque E., Rouleau M. Pharmacogenomics of Human Uridine Diphospho-Glucuronosyltransferases and Clinical Implications // Clin. Pharmacol. Ther. 2014. Vol. 96, № 3. P. 324–339.

Glucuronidation by uridine diphospho-glucurbnosyltransferase enzymes (UGTs) is a major phase II biotransformation pathway and, complementary to phase I metabolism and membrane transport, one of the most important cellular defense mechanisms responsible for the inactivation of therapeutic drugs, other xenobiotics, and endogenous molecules. Interindividual variability in UGT pathways is significant and may have profound pharmacological and toxicological implications. Several genetic and genomic processes underlie this variability and are discussed in relation to drug metabolism and diseases such as cancer.


44. Gupta S., Jhawat V. Quality by design (QbD) approach of pharmacogenomics in drug designing and formulation development for optimization of drug delivery systems // J. Control. Release. 2017. Vol. 245. P. 15–26.

Conventional approaches of drug discovery are very complex, costly and time consuming. But after the completion of human genome project, applications of pharmacogenomics in this area completely revolutionize the drug discovery and development process to produce a quality by design (QbD) approach based products. The applications of two areas of pharmacogenomics i.e. structural and functional pharmacogenomics excel the drug discovery process by employing genomic data in drug target identification and evaluation, lead optimization via high throughput screening, evaluation of drug metabolizing enzymes, drug transporters and drug receptors using computer aided technique and bioinformatics library data base. Pharmacogenomics also provides an important and reliable basis for evaluation and optimization of the dosage forms as well as repositioning of failed drugs for the treatment of new disease. Various dosage forms of category of drugs such as anticancer drugs, vaccines, gene and DNA delivery systems and immunological agents can be easily evaluated based on the genetic markers of the related disease. The effect of different formulation polymers on pharmacokinetic and pharmacodynamic properties of drugs can be assessed easily and therefore it plays an important role in formulation optimization. However, current applications of pharmacogenomics in drug discovery and formulation optimization are very limited because of costly and non accessible techniques for everyone, but in future, with the advancement in the technology; the application of genomic data in drug discovery will provide us with innovative, safer and more efficacious medicines.


45. Hall J.L., Palacio R.J., Meslin E.M. Genetics and Coronary Heart Disease // Coronary Heart Disease / ed. Vlodaver Z., Wilson R.F., Garry D.J. Springer US, 2012. P. 199–217.

Coronary heart disease (CHD) is the single leading cause of death in America, accounting for about one of every five deaths [1]. Family history of premature parental CHD is associated with a twofold increased risk of cardiovascular disease, making it vital that providers know their patients’ histories. For patients who do not know their family history, genetic testing is being considered as a means to someday fill this gap and will also increase the focus on prevention, provide better diagnostics, and help direct treatment options. This chapter summarizes findings about genes associated with CHD and raises practical and ethical issues that need to be addressed as this field of genetics evolves and before genetic testing at clinics becomes commonplace.


46. Harper A.R., Topol E.J. Pharmacogenomics in clinical practice and drug development // Nat. Biotechnol. 2012. Vol. 30, № 11. P. 1117–1124.

Genome-wide association studies (GWAS) of responses to drugs, including clopidogrel, pegylated-interferon and carbamazepine, have led to the identification of specific patient subgroups that benefit from therapy. However, the identification and replication of common sequence variants that are associated with either efficacy or safety for most prescription medications at odds ratios (ORs) > 3.0 (equivalent to > 300% increased efficacy or safety) has yet to be translated to clinical practice. Although some of the studies have been completed, the results have not been incorporated into therapy, and a large number of commonly used medications have not been subject to proper pharmacogenomic analysis. Adoption of GWAS, exome or whole genome sequencing by drug development and treatment programs is the most striking near-term opportunity for improving the drug candidate pipeline and boosting the efficacy of medications already in use.


47. Ho M.K., Tyndale R.F. Overview of the pharmacogenomics of cigarette smoking // Pharmacogenomics J. 2007. Vol. 7, № 2. P. 81–98.

Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.


48. Horstmann S., Binder E.B. Pharmacogenomics of antidepressant drugs // Pharmacol. Ther. 2009. Vol. 124, № 1. P. 57–73.

While antidepressant pharmacotherapy is an effective treatment of depression, it is still hampered by the slow onset of appreciable clinical improvement and a series of side effects. Moreover, a substantial group of patients does not achieve remission or fails to respond at all. One possible source accounting for these variations in treatment outcome are genetic differences. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. This manuscript summarizes findings related to the pharmacogenetics of genes involved in the pharmacokinetics as well as pharmacodynamics of antidepressants to date. Illustrated by examples from current candidate gene- and whole genome association studies, this manuscript critically discusses aspects of pharmacogenetic studies in antidepressant response related to study design and clinical relevance.


49. Ishikawa T. et al. Emerging New Technologies in Pharamcogenomics: Rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1) // Pharmacol. Ther. 2010. Vol. 126, № 1. P. 69–81.

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters as well as drug-metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and, by extension, their overall pharmacological effects. There are an increasing number of reports addressing genetic polymorphisms of drug transporters. A key requirement for the development of individualized medicine or personalized therapy is the ability to rapidly and conveniently test patients for genetic polymorphisms and/or mutations. We have recently developed a rapid and cost-effective method for single nucleotide polymorphism (SNP) detection, named Smart Amplification Process 2 (SmartAmp2), which enables us to detect genetic polymorphisms or mutations in 30 to 45 min under isothermal conditions without DNA isolation and PCR amplification. Furthermore, high-speed functional screening, quantitative structure-activity relationship (QSAR) analysis, and molecular dynamic (MD) simulation methods have been developed to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function and substrate specificity. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. This review addresses such new methods for validating genetic polymorphisms of human ABC transporter ABCB1 (P-gp/MDR1) which is critically involved in the pharmacokinetics of drugs.


50. Isvoran A. et al. Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism // Drug Discov. Today. 2017. Vol. 22, № 2. P. 366–376.

Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism. We summarize current advances in the molecular modeling of CYP2C polymorphisms and discuss the structural bases and molecular mechanisms of amino acid variants of CYP2C members that affect drug metabolism.


51. Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine // Pharmacogenomics J. 2006. Vol. 6, № 3. P. 162–165.

Pharmacogenetics arose with studies of single genes, which had major effects on the action of particular drugs. It turned into pharmacogenomics through realization that the controls of most drug responses are multifactorial. Then, variable gene expression posed new problems, for example what do drugs do to genes, or how useful is any genetic pretesting of a person? A common disease may be caused by different groups of genes in different people, who therefore require different drugs for treatment. Personlized medicine is currently represented by a physician's attention to a patients age, sex, or ethnic backround, that is groups showing smaller genetic variation than is typical for general humanity. Occasionally, there is also the use of single-gene pretesting of a patient before drug administration. Over time, improvements in multigenic testing promise to increase the role of personalized medicine. However, the many pharmacogenomic complexities, and particularly time-dependent changes of gene expression, will never allow personalized medicine to become an error-free entity.


52. Keun H.C. Metabonomic modeling of drug toxicity // Pharmacol. Ther. 2006. Vol. 109, № 1–2. P. 92–106.

Global metabolic profiling (metabonomics/metabolomics) has shown particular promise in the area of toxicology and drug development. In both preclinical screening and mechanistic exploration, metabolic profiling can offer rapid, noninvasive toxicological information that is robust and reproducible, with little or no added technical resources to existing studies in drug metabolism and toxicity. In this review, the study design and analytical technology required for metabonomics are discussed, along with key examples of how fundamental questions in drug development can be addressed. Strategies for metabonomic data analysis in toxicity assessment are detailed in both principle and practice, together with a description of toxicologically relevant metabolic biomarkers. Extended into the assessment of efficacy and toxicity in the clinic, metabonomics may prove crucial in making personalized therapy and pharmacogenomics a reality.


53. Knapman A., Connor M. Cellular signalling of non-synonymous single-nucleotide polymorphisms of the human mu-opioid receptor (OPRM1) // Br. J. Pharmacol. 2015. Vol. 172, № 2. P. 349–363.

There is significant variability in individual responses to opioid drugs, which is likely to have a significant genetic component. A number of non-synonymous single-nucleotide polymorphisms (SNPs) in the coding regions of the -opioid receptor gene (OPRM1) have been postulated to contribute to this variability. Although many studies have investigated the clinical influences of these -opioid receptor variants, the outcomes are reported in the context of thousands of other genes and environmental factors, and we are no closer to being able to predict individual response to opioids based on genotype. Investigation of how -opioid receptor SNPs affect their expression, coupling to second messengers, desensitization and regulation is necessary to understand how subtle changes in receptor structure can impact individual responses to opioids. To date, the few functional studies that have investigated the consequences of SNPs on the signalling profile of the -opioid receptor in vitro have shown that the common N40D variant has altered functional responses to some opioids, while other, rarer, variants display altered signalling or agonist-dependent regulation. Here, we review the data available on the effects of -opioid receptor polymorphisms on receptor function, expression and regulation in vitro, and discuss the limitations of the studies to date. Whether or not -opioid receptor SNPs contribute to individual variability in opioid responses remains an open question, in large part because we have relatively little good data about how the amino acid changes affect -opioid receptor function. Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit


54. Korngiebel D.M., Thummel K.E., Burke W. Implementing Precision Medicine: The Ethical Challenges // Trends Pharmacol. Sci. 2017. Vol. 38, № 1. P. 8–14.

Precision medicine aims to individualize care by understanding differences in genetics, lifestyle, and environment. Pharmacogenomics and cancer genetics represent two promising areas for this approach. Pharmacogenomic tests have the potential to direct drug prescribing to increase safety and effectiveness because individuals vary on a genetic basis in their response to many drugs. Similarly, tests to identify people with an inherited cancer risk can guide prevention. For both, a few tests have entered clinical practice and more are under development. Implementation challenges include the limited evidence base available to guide clinical use and the lack of data from diverse populations. Accordingly, ongoing research should prioritize procedures that enhance the trustworthiness of clinical practice guidelines and create decision support for clinicians and patients that address their needs and accommodate flexibility. Each step involves choices with ethical implications.


55. Laje G., McMahon F.J. Genome-wide association studies of antidepressant outcome: A brief review // Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2011. Vol. 35, № 7. P. 1553–1557.

Genome-wide association studies (GWAS) of antidepressant treatment outcome have been at the forefront of psychiatric pharmacogenetics. Such studies may ultimately help match medications with patients, maximizing efficacy while minimizing adverse effects. The hypothesis-free approach of the GWAS has the advantage of interrogating genes that otherwise would have not been considered as candidates due to our limited understanding of their function, and may also uncover important regulatory variation within the large regions of the genome that do not contain protein-coding genes. Three independent samples have so far been studied using a genome-wide approach: The Sequenced Treatment Alternatives to Relieve Depression sample (STAR*D) (n = 1953), the Munich Antidepressant Response Signature (MARS) sample (n = 339) and the Genome-based Therapeutic Drugs for Depression (GENDEP) sample (n = 706). None of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed. This review discusses the published GWAS studies, their strengths, limitations, and possible future directions.


56. Leung E.L. et al. Network-based drug discovery by integrating systems biology and computational technologies // Brief. Bioinform. 2013. Vol. 14, № 4. P. 491–505.

Network-based intervention has been a trend of curing systemic diseases, but it relies on regimen optimization and valid multi-target actions of the drugs. The complex multi-component nature of medicinal herbs may serve as valuable resources for network-based multi-target drug discovery due to its potential treatment effects by synergy. Recently, robustness of multiple systems biology platforms shows powerful to uncover molecular mechanisms and connections between the drugs and their targeting dynamic network. However, optimization methods of drug combination are insufficient, owning to lacking of tighter integration across multiple '-omics' databases. The newly developed algorithm- or network-based computational models can tightly integrate '-omics' databases and optimize combinational regimens of drug development, which encourage using medicinal herbs to develop into new wave of network-based multi-target drugs. However, challenges on further integration across the databases of medicinal herbs with multiple system biology platforms for multi-target drug optimization remain to the uncertain reliability of individual data sets, width and depth and degree of standardization of herbal medicine. Standardization of the methodology and terminology of multiple system biology and herbal database would facilitate the integration. Enhance public accessible databases and the number of research using system biology platform on herbal medicine would be helpful. Further integration across various '-omics' platforms and computational tools would accelerate development of network-based drug discovery and network medicine.


57. Li E.C. et al. Drug-Induced QT-Interval Prolongation: Considerations for Clinicians // Pharmacotherapy. 2010. Vol. 30, № 7. P. 684–701.

Drug-induced proarrhythmia is a frequently encountered clinical problem and a leading cause for withdrawal or relabeling of prescription drugs. Suppression of the rapid component of the delayed rectifier potassium current, I(Kr), represents the principal pharmacodynamic mechanism leading to heterogeneous prolongation of the ventricular action potential and prolongation of the QT interval clinically. However, the risk of proarrhythmia by QT-interval-prolonging drugs is variable and critically dependent on several factors leading to multiple reductions in the cardiac repolarization reserve. As antiarrhythmic drugs that prolong the QT interval are usually aggressively managed with continuous electrocardiogram monitoring and screening for drug interactions when administered to patients who have a high risk of sudden cardiac death, their risk of mortality is not increased. However, noncardiovascular QT-interval-prolonging drugs, which often produce less QT-interval prolongation compared with antiarrhythmic drugs, are found to be associated with increased rates of death in patients who have a markedly lower de novo risk of sudden cardiac death. Thus, it is important for clinicians, particularly pharmacists, to be cognizant of the levels of risk associated with varying degrees of QT-interval prolongation caused by drugs so that they can develop strategies to either prevent or reduce the risk of proarrhythmias.


58. Lin E. et al. Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder // Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2009. Vol. 33, № 7. P. 1167–1172.

Background: Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A: serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD). Methods: Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2 weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene-gene interactions. Results: Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value = 0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene-gene interaction (P-value = 0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value = 0.015) among GNB3, HTR2A, and SLC6A4. Conclusions: These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response.


59. Li-Wan-Po A. et al. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17 // Br. J. Clin. Pharmacol. 2010. Vol. 69, № 3. P. 222–230.

center dot CYP2C19 polymorphisms may have clinical consequences in relation to drugs extensively metabolized by the enzyme. center dot Recently a new variant CYP2C19*17 was discovered. center dot Unlike other commonly studied variant alleles, notably CYP2C19*2 and CYP2C19*3, which are defective, CYP2C19*17 is associated with enhanced enzyme activity and three CYP2C19 phenotypes have been suggested: ultrarapid metabolizers (UM), extensive metabolizers (EM) and poor metabolizers (PM). center dot There appears to be interethnic variability in the prevalence of the CYP2C19*17 allele. WHAT THIS STUDY ADDS center dot We provide the first critical quantitative review of this rapidly developing area of research to serve as a basis for subsequent research and overviews. center dot We summarize data on population prevalence and functional effects of CYP2C19*17. center dot We argue on the basis of current evidence that potentially significant clinical effects are unlikely except for drugs with very narrow therapeutic windows. Of studied substrates, only clopidogrel may fall into this category. Even then, only homozygotes of the variant allele are likely to be at significantly increased risk. center dot The assignment of CYP2C19*17 homozygotes as EM, rather than UM, is adequate as the metabolic ratios of all probe drugs studied so far overlap completely the range of values seen in wild-type homozygotes. center dot The implications of CYP2C19*17 on the clinical effects of tamoxifen require further study. AIMS Cytochrome P450 2C19 metabolizes many important drugs. In 2006, a variant allele (CYP2C19*17) associated with increased activity was discovered, but its likely clinical significance is controversial. Investigators disagree about the phenotype to be assigned to the two CYP2C19*17 genotypes. The aim of this study was to provide a critical summary, helpful to prescribers. METHODS We searched MEDLINE for papers on the allele from 2006 and then undertook historical searches through the reference lists of papers retrieved. The relevant information was critically assessed and summarized. RESULTS CYP2C19*17 was associated with increased enzymic activity. Substrates studied were omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel. Most studies used pharmacokinetic variables as outcome measure. For clopidogrel, activated by CYP2C19, pharmacodynamic consequences focused on platelet aggregation. While for most pharmacokinetic parameters of the substrates studied the average value was altered, the range of values showed mostly complete overlap for CYP2C19*1/*17 heterozygotes and wild-type homozygotes. Even for CYP2C19*17 homozygotes, the absolute effect was modest compared with the effect of previously identified loss-of-function alleles. In Helicobacter pylori eradication CYP2C19*2 carriage was associated with an altered eradication rate (odds ratio 4.20, 95% confidence interval 1.23, 16.44) relative to the wild-type, but CYP2C19*17 homozygosity was not. Prevalence of the variant allele was typically < 5% in Asians and about four times higher in White and African populations. CONCLUSIONS Assignment of CYP2C19*17 homozygotes as extensive metabolizers rather than ultrarapid metabolizers is adequate. CYP2C19*17 genotyping is unlikely to have clinical utility except for drugs with very narrow therapeutic indices.


60. LLerena A. Population pharmacogenetics and global health // Drug Metabolism and Personalized Therapy. 2015. Vol. 30, № 2. P. 73–74.

The results of these studies will improve the clinical use of available drugs and improve new drugs under development by promoting the importance of pharmacovigilance programs and recommended drug dosage regimens for specific populations affected by relevant global health diseases. Further, the results will produce the knowledge required for implementing pharmacogenetics and personalized medicine into relevant public and global health affairs. In conclusion, the costs of the most relevant global diseases for individuals, families and society could be decreased by adapting drug recommendations to the characteristics of each population.


61. Lopez-Santillan M. et al. Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene // Drug Metabolism and Personalized Therapy. 2017. Vol. 32, № 1. P. 1–9.

Acute lymphoblastic leukemia (ALL) is a major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients who experience severe adverse events. L-Asparaginase is an effective antineoplastic agent used in chemotherapy of ALL. Despite its indisputable indication, hypersensitivity reactions are common. In those cases, discontinuation of treatment is usually needed and anti-asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect. Till now, six pharmacogenetic studies have been performed in order to elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity. In this review we have summarized the results of those studies which describe the involvement of four different genes, being polymorphisms in the glutamate receptor, ionotropic, AMPA 1 (GRIA1) the most frequently associated with asparaginase hypersensitivity. We also point to new approaches focusing on epigenetics that could be interesting for consideration in the near future.


62. Lowery M.A., O’Reilly E.M. Genomics and pharmacogenomics of pancreatic adenocarcinoma // Pharmacogenomics J. 2012. Vol. 12, № 1. P. 1–9.

The last decade has brought significant advances in the development of molecularly targeted therapies for treatment of a variety of human malignancies. In contrast to other solid tumors, however, the impact of novel therapeutic strategies on clinical outcomes in patients with pancreatic adenocarcinoma (PAC) has been limited to date. Gemcitabine was established as a standard of care for treatment of advanced PAC in 1997 based on an observed improvement in clinical benefit as adjudicated principally by pain scores and analgesic consumption, and demonstration of an overall survival (OS) benefit in a randomized comparison with 5-fluorouracil (5-FU). Since then, multiple agents targeting oncogenic signaling pathways and mediators of angiogenesis have failed to improve outcomes in phase III clinical trials when compared with gemcitabine monotherapy. An exception to this is the anti-epidermal growth factor receptor therapy erlotinib, which yielded a survival benefit in patients with advanced disease in combination with gemcitabine compared with gemcitabine alone, although this was a marginal incremental improvement for which the clinical significant has been heavily debated. More recently, the most significant therapeutic advance in PAC has come from the combination of several cytotoxic agents; infusional 5-FU, irinotecan and oxaliplatin. This combination chemotherapy regimen, known as FOLFIRINOX, improved survival in patients with an excellent functional status and stage IV disease by 4.3 months compared with gemcitabine alone. This improvement in survival did come at the cost expectedly of a significant increase in toxicities, including gastrointestinal and hematologic particularly. Other gemcitabine-based combination chemotherapy regimens including gemcitabine and platinum analogs and gemcitabine and capecitabine have consistently shown an increased response rate but no OS benefit in individual trials; albeit pooled and meta-analyses have indicated a survival benefit in good performance status patient for both these cytotoxic combinations. Accordingly, the 5-year survival for patients with PAC remains <5%, with an annual disease-specific mortality which approaches the incidence. The challenge remains therefore, to develop more effective systemic therapies against this challenging malignancy. Recent progress toward understanding the genetic events in the development of PAC, in combination with advances in the field of pharmacogenomics offer hope that we may build on achievements to-date to develop more effective therapeutic strategies for PAC in years to come. The


63. Ma Q., Lu A.Y.H. Pharmacogenetics, Pharmacogenomics, and Individualized Medicine // Pharmacol. Rev. 2011. Vol. 63, № 2. P. 437–459.

Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. For more than 5 decades, studies of pharmacogenetics have provided ample examples of causal relations between genotypes and drug response to account for phenotypic variations of clinical importance in drug therapy. The convergence of pharmacogenetics and human genomics in recent years has dramatically accelerated the discovery of new genetic variations that potentially underlie variability in drug response, giving birth to pharmacogenomics. In addition to the rapid accumulation of knowledge on genome-disease and genome-drug interactions, there arises the hope of individualized medicine. Here we review recent progress in the understanding of genetic contributions to major individual variability in drug therapy with focus on genetic variations of drug target, drug metabolism, drug transport, disease susceptibility, and drug safety. Challenges to future pharmacogenomics and its translation into individualized medicine, drug development, and regulation are discussed. For example, knowledge on genetic determinants of disease pathogenesis and drug action, especially those of complex disease and drug response, is not always available. Relating the many gene variations from genomic sequencing to clinical phenotypes may not be straightforward. It is often very challenging to conduct large scale, prospective studies to establish causal associations between genetic variations and drug response or to evaluate the utility and cost-effectiveness of genomic medicine. Overcoming the obstacles holds promise for achieving the ultimate goal of effective and safe medication to targeted patients with appropriate genotypes.


64. MacKenzie M., Hall R. Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review // Can. J. Anesth. 2017. Vol. 64, № 1. P. 45–64.

Purpose Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. We selected relevant literature to illustrate the important concepts contained within. Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach. Genetic variability in response to drugs may occur as a result of alterations of drug-metabolizing (cytochrome P [CYP]) enzymes, receptors, and transport proteins leading to enhancement or delay in the therapeutic response. Of relevance to the ICU, genetic variation in CYP-450 isoenzymes results in altered effects of midazolam, fentanyl, morphine, codeine, phenytoin, clopidogrel, warfarin, carvedilol, metoprolol, HMG-CoA reductase inhibitors, calcineurin inhibitors, non-steroidal anti-inflammatory agents, proton pump inhibitors, and ondansetron. Changes in cholinesterase enzyme function may affect the disposition of succinylcholine, benzylisoquinoline muscle relaxants, remifentanil, and hydralazine. Genetic variation in transport proteins leads to differences in the response to opioids and clopidogrel. Polymorphisms in drug receptors result in altered effects of beta-blockers, catecholamines, antipsychotic agents, and opioids. Genetic variation also contributes to the diversity and incidence of diseases and conditions such as sepsis, malignant hyperthermia, drug-induced hypersensitivity reactions, cardiac channelopathies, thromboembolic disease, and congestive heart failure. Application of pharmacogenetics and pharmacogenomics has seen improvements in drug therapy. Ongoing study and incorporation of these concepts into clinical decision making in the ICU has the potential to affect patient outcomes.


65. Magdy T., Burmeister B.T., Burridge P.W. Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing? // Pharmacol. Ther. 2016. Vol. 168. P. 113–125.

The cardiotoxicity of certain chemotherapeutic agents is now well-established, and has led to the development of the field of cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocyte death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7-28% for trastuzumab, or 5-30% for paclitaxel. For tyrosine kinase inhibitors, QT prolongation and arrhythmia, ischemia and hypertension have been reported in 2-35% of patients. Furthermore, newly introduced chemotherapeutic agents are commonly used as part of changed combinational regimens with significantly increased incidence of cardiotoxicity. It is widely believed that the mechanism of action of these drugs is often independent of their cardiotoxicity, and the basis for why these drugs specifically affect the heart has yet to be established. The genetic rationale for why certain patients experience cardiotoxicity whilst other patients can tolerate high chemotherapy doses has proven highly illusive. This has led to significant genomic efforts using targeted and genome-wide association studies (GWAS) to divine the pharmacogenomic cause of this predilection. With the advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the putative risk and protective role of single nucleotide polymorphisms (SNPs) can now be validated in a human model. Here we review the state of the art knowledge of the genetic predilection to chemotherapy-induced cardiotoxicity and discuss the future for establishing and validating the role of the genome in this disease.


66. Mahajan P. et al. Clinical applications of pharmacogenomics guided warfarin dosing // Int. J. Clin. Phar,. 2011. Vol. 33, № 1. P. 10–19.

Aim of the Review To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. Method We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. Results Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. Conclusion Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use.


67. Mahajan P. et al. Clinical applications of pharmacogenomics guided warfarin dosing // Int. J. Clin. Phar,. 2013. Vol. 35, № 3. P. 359–368.

Aim of the Review To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. Method We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. Results Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. Conclusion Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use.


68. Mahajan P.B. Recent Advances in Application of Pharmacogenomics for Biotherapeutics // AAPS J. 2016. Vol. 18, № 3. P. 605–611.

Biotherapeutics (BTs), one of the fastest growing classes of drug molecules, offer several advantages over the traditional small molecule pharmaceuticals because of their relatively high specificity, low off-target effects, and biocompatible metabolism, in addition to legal and logistic advantages. However, their clinical utility is limited, among other things, by their high immunogenic potential and/or variable therapeutic efficacy in different patient populations. Both of these issues, also commonly experienced with small molecule drugs, have been addressed effectively in a number of cases by the successful application of pharmacogenomic tools and approaches. In this introductory article of the special issue, we review the current state of application of pharmacogenomics to BTs and offer suggestions for further expansion of the field.


69. Malentacchi F. et al. Is laboratory medicine ready for the era of personalized medicine? A survey addressed to laboratory directors of hospitals/academic schools of medicine in Europe // Drug Metabolism and Personalized Therapy. 2015. Vol. 30, № 2. P. 121–128.

Developments in “-omics” are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of-the-art knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach.


70. Mangravite L.M., Thorn C.F., Krauss R.M. Clinical implications of pharmacogenomics of statin treatment // Pharmacogenomics J. 2006. Vol. 6, № 6. P. 360–374.

Although, statin pharmacogenetics is still in its infancy, the consensus based on current evidence is that genetic testing to assist in selecting a particular statin and/or dosing regimen is not clinically warranted. There are several reasons for this opinion. Statin therapy is so well tolerated in the majority of patients that the need to use additional testing to avoid deleterious side effects is relatively small. Moreover patients should be monitored for signs of hepatic or muscle toxicity to avoid more severe adverse reactions. In addition, patients on statin therapy should have lipid levels monitored so that submaximal response can be improved by increased dosage. Another major concern is that nearly all studies of pharmacogenetics of statin response reported to date have been underpowered and replication of positive results is lacking. Finally, most of these studies have examined associations of individual genetic polymorphisms with treatment response. Although genetic differences may prove a significant source of response variability, this is unlikely to be due to any single gene. Rather, the compound effects of multiple genetic variants are more likely to be responsible. Most studies have examined a small number of variants in a single or small number of genes – often one variant in one gene – and have reported the resultant outcomes based on small patient populations.


71. Marcsisin S.R., Reichard G., Pybus B.S. Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art // Pharmacol. Ther. 2016. Vol. 161. P. 1–10.

Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75 years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.


72. Maronas O. et al. Progress in pharmacogenetics: consortiums and new strategies // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 1. P. 17–23.

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.


73. Masuda S., Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients // Pharmacol. Ther. 2006. Vol. 112, № 1. P. 184–198.

Calcineurin inhibitors, tacrolimus (FK506) and cyclosporine (ciclosporin A), are the primary immunosuppressive agents used on recipients of organ transplantations. The hepatic metabolism of these drugs by cytochrome P450 IIIA (CYP3A) subfamilies is considered a major eliminating process. The intestinal efflux-pump P-glycoprotein (Pgp) (multidrug resistance 1 [MDR1], ATP-binding cassette B1 [ABCB1]) and CYP3A4 have been demonstrated as important for the bioavailability of drugs, so called "absorptive barriers". Recently, an important role for CYP3A5 in the intestine for the oral clearance of drugs has been identified. Both tacrolimus and cyclosporine are substrates of Pgp, CYP3A4 and CY-P3A5, and therefore, these molecules are potential pharmacokinetic factors with which to establish personalized dosage regimens for these drugs. Although the effect of single nucleotide polymorphisms in the MDR1/ABCB1 and CYP3A5 genes on the pharmacokinetics of immunosuppressant has been widely examined, some contradictions have been emerged. In living-donor liver transplant (LDLT) patients, the intestinal mRNA expression level of MDR1 and CYP3A5 genotyping both in the native intestine and in the grafted liver are suggested to be potential pharmacokinetic factors for adjusting initial dosage and predicting post-operative variation in the pharmacokinetics of tacrolimus. We review the pharmacokinetic and pharmacodynamic characteristics of these drugs including the large pharmacokinetic variation and potential individualized dosage adjustments based on the genomic information of transporters and metabolic enzymes as well as classical pharmacokinetic analyses based on therapeutic drug monitoring (TDM).


74. Matthews S.J., Lancaster J.W. Telaprevir: A Hepatitis C NS3/4A Protease Inhibitor // Clin. Ther. 2012. Vol. 34, № 9. P. 1857–1882.

Background: Telaprevir is a hepatitis C NS3/4A protease inhibitor approved by the US Food and Drug Administration as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. Objective: The article reviews published literature on telaprevir, including its chemistry, mechanism of action, resistance, pharmacodynamic and pharmacokinetic properties, drug interactions, therapeutic efficacy, HIV/HCV coinfection, pharmacogenomics, adverse events, pharmacoeconomics, and dosing and administration. Methods: English-language literature was included. Searches of MEDLINE and BIOSIS databases from 1975 through January 2012 were performed. Emphasis was placed on reference citations involving clinical trials, randomized controlled trials, and research in humans. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from recent scientific meetings. Search terms included, but were not limited to, telaprevir, VX-950, hepatitis C virus genotype 1, resistance, pharmacology, pharmacokinetics, pharmacodynamics, drug interactions, pharmacogenomics, adverse events, and therapeutic use. Results: Review of the databases revealed 471 publications/abstracts on this subject. Of these, 85 were chosen based on the review criteria. Two Phase III studies investigated the efficacy and tolerability of telaprevir administered for 12 weeks (T12) when used with peginterferon alfa and ribavirin (PR) in treatment-naive subjects. The ADVANCE study reported that patients who had an extended rapid virologic response (eRVR; an undetectable HCV RNA level at both 4 and 12 weeks of treatment) with triple therapy could be treated with PR for a total of 24 weeks (T12PR24 group) versus standard PR treatment for 48 weeks (PR48 group [control]). The proportions of patients who achieved sustained virologic response (SVR; undetectable HCV RNA concentration at 24 weeks after the completion of therapy) in the T12PR24 and PR48 groups were 89% and 44%, respectively. The ILLUMINATE study reported T12PR24 was noninferior to T12PR48 in patients with an eRVR to combination therapy. In the REALIZE study, patients with a history of relapse responded well to T12PR48 compared with PR48 (SVR, 83% vs 24%). Telaprevir is a substrate/inhibitor of cytochrome P450 (CYP3A4) and a substrate/inhibitor of P-glycoprotein and poses an important risk for drug interactions. Adverse drug events (ADEs) reported most commonly with triple therapy compared with the T or PR regimen alone were rash, pruritus, nausea, diarrhea, and anemia. The serious AEs most commonly reported during T + PR therapy were anemia, rash, and pruritus. Two reports concluded that T combined with PR was not cost-effective due to the high cost of telaprevir. One study reported that the combination of T + PR would be cost-effective if the treatment rate of HCV genotype 1 infected patients reached 50%. Conclusion: Including telaprevir as part of triple therapy for the management of chronic HCV genotype 1 infection significantly increases the likelihood of achieving an SVR over standard dual drug therapy (PR) in both treatment-naive and -experienced patients. However, due to the high cost, the use of triple therapy with telaprevir will likely be limited to patient groups known to respond poorly to dual therapy.


75. Merali Z., Ross S., Pare G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect // Drug Metabolism and Drug Interactions. 2014. Vol. 29, № 3. P. 143–151.

Human carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are serine esterases responsible for the hydrolysis of ester and amide bonds present in a number of pharmaceutical products. Several common genetic variants of the CES1 and CES2 genes have been shown to influence drug metabolism and clinical outcomes. Polymorphisms of the CES1 gene have been reported to affect the metabolism of dabigatran etexilate, methylphenidate, oseltamivir, imidapril, and clopidogrel, whereas variants of the CES2 gene have been found to affect aspirin and irinotecan. Although the findings of these studies may be preliminary, they demonstrate the potential clinical utility of CES polymorphisms; however, more research is required, especially with respect to CES2. In this review, we outline the functional, molecular, and genetic properties of CES1 and CES2, and highlight recent studies that have shown relations between CES1 and CES2 variants and contemporary pharmacotherapy.


76. Meslin E.M., Garba I. Biobanking and public health: is a human rights approach the tie that binds? // Hum. Genet. 2011. Vol. 130, № 3. P. 451–463.

Ethical principles guiding public health and genomic medicine are often at odds: whereas public health practice adopts collectivist principles that emphasize population-based benefits, recent advances in genomic and personalized medicine are grounded in an individualist ethic that privileges informed consent, and the balancing of individual risk and benefit. Indeed, the attraction of personalized medicine is the promise it holds out to help individuals get the "right medicine for the right problem at the right time." Research biobanks are an effective tool in the genomic medicine toolbox. Biobanking in public health presents a unique case study to unpack some of these issues in more detail. For example, there is a long history of using banked tissue obtained under clinical diagnostic conditions for later public health uses. But despite the collectivist approach of public health, the principles applied to the ethical challenges of biobanking (e.g. informed consent, autonomy, privacy) remain individualist. We demonstrate the value of using human rights as a public health ethics framework to address this tension in biobanking by applying it to two illustrative cases.


77. Molet J., Pohl M. Gene-based approaches in pain research and exploration of new therapeutic targets and strategies // Eur. J. Pharmacol. 2013. Vol. 716, № 1–3. P. 129–141.

Large panel of gene based techniques is used for many years specifically in the pain research field. From the first identification (cloning) of some "mythic" genes, such as those encoding opioid or capsaicin receptors allowing then the creation of first-generation knockout mice, to the today conditional (time, tissue, cell-type and even pathology-dependent) and regulatable modulation of a gene function, these approaches largely contributed to fundamental leaps forward in our understanding of the function of some proteins and of their interest as possible druggable targets. Perhaps one of the most remarkable evolution in the last years is the passage of these approaches from the bench to the patient; whether it concerns the identification or genes involved in inherited pain insensibility/susceptibility, the search for genetic markers of pain types, the individual pharmacogenomics or even the first gene therapy trials. From many possible variants of gene-grounded techniques used in pain research we focus here on gene knockouts and some recent developments, on viral vectors-based gene transfer and on transgenic models for the tracing of pain pathways. Through these selected examples we attempted to emphasize the immense potential of these approaches and their already well-recognized contribution in both the basic and clinical pain research.


78. Murphy D.L. et al. How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems // Neuropharmacology. 2008. Vol. 55, № 6. P. 932–960.

Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species: an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene: and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.


79. Najafzadeh M. et al. Barriers for integrating personalized medicine into clinical practice: A qualitative analysis // Am. J. Med. Genet. A. 2013. Vol. 161A, № 4. P. 758–763.

Personalized medicinetailoring interventions based on individual's genetic informationwill likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi-structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n=9) of physicians self-reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n=19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools.


80. Najafzadeh M. et al. Barriers to integrating personalized medicine into clinical practice: a best-worst scaling choice experiment // Genet. Med. 2012. Vol. 14, № 5. P. 520–526.

Purpose: As advances in genomics make genome sequencing more affordable, the availability of new genome-based diagnostic and therapeutic strategies (i.e., personalized medicine) will increase. This wave will hit front-line physicians who may be faced with a plethora of patients' expectations of integrating genomic data into clinical care. The objective of this study was to elicit the preferences of physicians regarding applying personalized medicine in their clinical practice as these strategies become available. Methods: Using a best-worst scaling (BWS) choice experiment, we estimated the relative importance of attributes that influence physicians' decisions for using personalized medicine. Six attributes were included in the BWS: type of genetic tests, training for genetic testing, clinical guidelines, professional fee, privacy protection laws, and cost of genetic tests. A total of 197 physicians in British Columbia completed the experiment. Using latent class analysis (LCA), we explored the physicians' heterogeneities in preferences. Results: "Type of genetic tests" had the largest importance, suggesting that the physicians' decision was highly influenced by the availability of genetic tests for patients' predisposition to diseases and/or drug response. "Training" and "guidelines" were the attributes with the next highest importance. LCA identified two classes of physicians. Relative to class 2, class 1 had a larger weight for the "type of genetic tests:" but smaller weights for "professional fee" and "cost of tests." Conclusion: We measured relative importance of factors that affect the decision of physicians to incorporate personalized medicine in their practice. These results can be used to design the policies for supporting physicians and facilitating the use of personalized medicine in the future.


81. Nakagawa H. et al. Ubiquitin-Mediated Proteasomal Degradation of ABC Transporters: a New Aspect of Genetic Polymorphisms and Clinical Impacts // J. Pharm. Sci. 2011. Vol. 100, № 9. P. 3602–3619.

The interindividual variation in the rate of drug metabolism and disposition has been known for many years. Pharmacogenomics dealing with heredity and response to drugs is a part of science that attempts to explain variability of drug responses and to search for the genetic basis of such variations or differences. Genetic polymorphisms of drug metabolizing enzymes and drug transporters have been found to play a significant role in the patients' responses to medication. Accumulating evidence demonstrates that certain nonsynonymous polymorphisms have great impacts on the protein stability and degradation, as well as the function of drug metabolizing enzymes and transporters. The aim of this review article is to address a new aspect of protein quality control in the endoplasmic reticulum and to present examples regarding the impact of nonsynonymous single-nucleotide polymorphisms on the protein stability of thiopurine S-methyltransferase as well as ATP-binding cassette (ABC) transporters including ABCC4, cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), ABCC11, and ABCG2. Furthermore, we will discuss the molecular mechanisms underlying posttranslational modifications (intramolecular and intermolecular disulfide bond formation and N-linked glycosylation) and ubiquitin-mediated proteasomal degradation of ABCG2, one of the major drug transporter proteins in humans.


82. Nebert D.W., Vesell E.S. Can personalized drug therapy be achieved? A closer look at pharmaco-metabonomics // Trends Pharmacol. Sci. 2006. Vol. 27, № 11. P. 580–586.

Between 1930 and 1990, several dozen high-penetrance, predominantly monogenic disorders were identified and characterized, which led some investigators to speculate that individualized drug treatment was just around the corner. Informative DNA tests were sought to determine genetic predisposition to toxicity and cancer, thereby identifying individuals in which a drug was likely to be effective and those at increased risk of drug toxicity. These assays represent the leading edge of phenotype-genotype association studies, which are a major goal of clinical pharmacology and pharmacogenomics. Because of the complexity of the genome, however, the task is more challenging than anticipated originally. In the past decade we have come to appreciate how difficult it is to determine unequivocally either an exact phenotype or genotype. In the near future it seems unlikely that, by themselves, either transcriptomics or proteomics will be particularly helpful in achieving individualized drug therapy. However, recent advances in metabonomics are exciting and show promise. In the future, and perhaps in combination with proteomics, metabonomics might complement genomics in achieving personalized drug therapy.


83. O’Connell G. et al. Schizophrenia risk genes: Implications for future drug development and discovery // Biochem. Pharmacol. 2011. Vol. 81, № 12. P. 1367–1373.

Present-day development of improved treatments for schizophrenia is hindered by uncertain models of disease, inter-individual response variability in clinical trials and a paucity of sensitive measures of treatment effects. Findings from genetic research emphasize the potential for schizophrenia risk genes to help develop focused treatments, discover new drug targets and provide markers of clinical subtypes. Advances in genetic technologies also provide novel modes of drug discovery in schizophrenia such as transcriptomics, epigenetics and transgenic animal models. In this review, we discuss proven and proposed ways risk genes can be used to enhance the development and discovery of treatments for schizophrenia and highlight key studies in these approaches.


84. Obeng A.O. et al. CYP2C19 Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics? // Pharmacotherapy. 2014. Vol. 34, № 7. P. 703–718.

Since its approval by the U. S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.


85. Olkkola K.T. et al. Does the pharmacology of oxycodone justify its increasing use as an analgesic? // Trends Pharmacol. Sci. 2013. Vol. 34, № 4. P. 206–214.

Oxycodone is a semisynthetic opioid analgesic that is increasingly used for the treatment of acute, cancer, and chronic non-malignant pain. Oxycodone was synthesized in 1917 but its pharmacological properties were not thoroughly studied until recently. Oxycodone is a fairly selective mu-opioid receptor agonist, but there is a striking discrepancy between the relatively low binding potential and G protein activation by oxycodone and its analgesic efficacy. It has been claimed that this is because of active metabolites and enhanced passage to the central nervous system by active transport. We critically review studies on the basic pharmacology of oxycodone and on its pharmacokinetics and pharmacodynamics in humans. In particular, the role of pharmacogenomics and population pharmacokinetics in understanding the properties of oxycodone is discussed in detail. We compare oxycodone with morphine, the standard opioid in clinical use.


86. Ortega S.S., Cara L.C.L., Salvador M.K. In silico pharmacology for a multidisciplinary drug discovery process // Drug Metabolism and Drug Interactions. 2012. Vol. 27, № 4. P. 199–207.

The process of bringing new and innovative drugs, from conception and synthesis through to approval on the market can take the pharmaceutical industry 8–15 years and cost approximately $1.8 billion. Two key technologies are improving the hit-to-drug timeline: high-throughput screening (HTS) and rational drug design. In the latter case, starting from some known ligand-based or target-based information, a lead structure will be rationally designed to be tested in vitro or in vivo. Computational methods are part of many drug discovery programs, including the assessment of ADME (absorption-distribution-metabolism-excretion) and toxicity (ADMET) properties of compounds at the early stages of discovery/development with impressive results. The aim of this paper is to review, in a simple way, some of the most popular strategies used by modelers and some successful applications on computational chemistry to raise awareness of its importance and potential for an actual multidisciplinary drug discovery process.


87. Parry H.M. et al. State of Play of Pharmacogenetics and Personalized Medicine in Heart Failure // Cardiovasc. Ther. 2013. Vol. 31, № 6. P. 315–322.

Heart failure is a common disease with high levels of morbidity and mortality. A large body of evidence guiding treatment shows prognostic benefit with beta-blockers and angiotensin-converting enzyme inhibitors, while diuretics are commonly prescribed for symptomatic benefit. Wide variation in drug response between clinically similar patients is a significant problem. Evidence suggests this may have a genetic component. Variation in candidate genes including the beta-1, beta-2, and alpha-2 adrenergic receptors, the renin-angiotensin-aldosterone pathway and genes involved in renal electrolyte handling with diuretics may be important. Single-nucleotide polymorphisms (SNPs) potentially influencing drug response include the Arg 389 Gly variant and the Ser 49 Gly variant in the beta-1 adrenergic receptor, the Arg 16 Gly, Gln 27 Glu, and Thr 164 Ile polymorphisms within the beta-2 adrenergic receptor, an insertion at the 287th base pair in the angiotensin-converting enzyme and the Gly 264 Ala mutation in the sodium chloride co-transporter. However, research addressing the clinical significance of these polymorphisms has yielded conflicting results that have had no influence on clinical practice. Genome-wide association studies may provide an alternative approach to discovering genetic variations influencing drug response, a relatively unchartered area in heart failure management. If future work in this area produces a strong case that variation in drug response has a specific and clinically meaningful genetic component, this could be used to guide drug dosing based on genotype; a step forward in the journey toward personally tailored medicine.


88. Passetti F., Ferreira C.G., Costa F.F. The impact of microRNAs and alternative splicing in pharmacogenomics // Pharmacogenomics J. 2009. Vol. 9, № 1. P. 1–13.

Pharmacogenomic studies emphasize the use of genomic information to enhance success in finding new medicines and also to improve those that are already used in clinics. Therefore, this field has a special interest in knowing how patients metabolize drugs depending on their genetic background. Most of the studies so far have focused on the impact of single genetic differences on drug metabolism. However, this may be only the tip of the iceberg in terms of how interpatient variability can influence the response to drugs. For example, control of gene expression by microRNAs (miRNAs) and alternative splicing are cellular mechanisms that have an effect on proteome diversity and have already been implicated in complex diseases such as cancer, arthritis and others. Changes in the sequence of a miRNA and/or variations in the miRNA target region of a transcript can have a major impact on post-transcriptional regulation. Events of alternative splicing can occur in more than half of the human genes, thereby changing the sequence of key proteins related to drug resistance, activation and metabolism. Furthermore, alternative splicing and miRNAs can work together to differentially control genes. This perspective article will highlight recent exciting discoveries in pharmacogenomics and also discuss how players such as miRNAs and alternative splicing may affect the way we design and apply future therapies.


89. Payami H., Factor S.A. Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson’s Disease. A Perspective // Neurotherapeutics. 2014. Vol. 11, № 1. P. 111–116.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a heterogeneous array of motor and non-motor features. Anti-PD drugs that are in use target only the motor symptoms, may lose efficacy over time, and can cause serious adverse effects such as dyskinesia and psychosis. There are currently no preventative or disease modifying treatments. All attempts to develop disease modifying drugs have failed. Pharmacogenomics (PGx) has the potential to change the way new drugs are developed and the way drugs are prescribed. By using genetic markers that correlate with, and can therefore predict drug response, clinical trials can be designed to be enriched with individuals who are most likely to benefit from the drug, maximizing drug's efficacy, minimizing its adverse effects, and boosting the odds of successful drug discovery. Clinical application of PGx will help physicians to quickly and accurately determine the right drugs and the right doses for individuals, avoiding the lengthy trial and error approaches and adverse effects. In combination with known protective factors such as nicotine and caffeine, PGxmay enable development of personalized methods for PD prevention and, by extension, care.


90. Peiro A.M. et al. Pharmacogenomics in pain treatment // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 3. P. 131–142.

The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics. However, uptake of this information has been slow due in large part to the lack of robust evidences demonstrating clinical utility. Furthermore, novel therapies, including targeting of epigenetic changes and gene therapy-based approaches are further broadening future options for the treatment of chronic pain. The aim of this article is to review the evidences behind pharmacogenetics (PGx) to individualize therapy (boosting the efficacy and minimizing potential toxicity) and genes implicated in pain medicine, in two parts: (i) genetic variability with pain sensitivity and analgesic response; and (ii) pharmacological concepts applied on PGx.


91. Peltz G. Can “humanized” mice improve drug development in the 21st century? // Trends Pharmacol. Sci. 2013. Vol. 34, № 5. P. 255–260.

Chimeric mice, which have human hepatocytes engrafted in their liver, have been used to study human drug metabolism and pharmacodynamic responses for nearly 20 years. However, there are very few examples where their use has prospectively impacted the development of a candidate medication. Here, three different chimeric mouse models and their utility for pharmacology studies are evaluated. Several recent studies indicate that using these chimeric mouse models could help to overcome traditional (predicting human-specific metabolites and toxicities) and 21st century problems (strategies for personalized medicine and selection of optimal combination therapies) in drug development. These examples suggest that there are many opportunities in which the use of chimeric mice could significantly improve the quality of preclinical drug assessment.


92. Peters B.J.M. et al. Methodological and statistical issues in pharmacogenomics // J. Pharm. Pharmacol. 2010. Vol. 62, № 2. P. 161–166.

Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways.


93. Pirmohamed M. et al. Oral anticoagulation: a critique of recent advances and controversies // Trends Pharmacol. Sci. 2015. Vol. 36, № 3. P. 153–163.

There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.


94. Pirmohamed M. Pharmacogenetics: past, present and future // Drug Discov. Today. 2011. Vol. 16, № 19–20. P. 852–861.

The subject area of pharmacogenetics, also known as pharmacogenomics, has a long history. Research in this area has led to fundamental discoveries, which have helped our understanding of the reasons why individuals differ in the way they handle drugs, and ultimately in the way they respond to drugs, either in terms of efficacy or toxicity. However, not much of this knowledge has been translated into clinical practice, most drug-gene associations that have some evidence of clinical validity have not progressed to clinical settings. Advances in genomics since 2000, including the ready availability of data on the variability of the human genome, have provided us with unprecedented opportunities to understand variability in drug responses, and the opportunity to incorporate this into patient care. This is only likely to occur with a systematic approach that evaluates and overcomes the different translational gaps in taking a biomarker from discovery to clinical practice. In this article, I explore the history of pharmacogenetics, appraise the current state of research in this area, and finish off with suggestions for progressing in the field in the future.


95. Prasad K., Breckenridge A. Pharmacogenomics: a new clinical or regulatory paradigm? European experiences of pharmacogenomics in drug regulation and regulatory initiatives // Drug Discov. Today. 2011. Vol. 16, № 19–20. P. 867–872.

Are regulatory agencies and processes up to speed? This is an often asked question. Recent advances in science and the improved knowledge of the human genome have a considerable influence on drug development and their impact on the regulatory aspect is also significant for several reasons, including changing stakeholder expectations and treatment paradigms. One of the challenges faced by the regulators is the need to adapt regulatory processes to accommodate the newer methodologies and techniques while ensuring that the biomarkers, tests and/or diagnostics, and the clinical trials are appropriate and fit for purpose. The change in emphasis in pharmacological treatment from a phenotype-based approach to newer methods is attractive but is it ready for universal adoption? This paper details some of the regulatory responses to the developments in this area.


96. Ramos M. et al. Pharmacogenetic studies: a tool to improve antidepressant therapy // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 4. P. 197–204.

The World Health Organization (WHO) predicts that major depressive disorder (MDD) will be the second leading cause of death and disability by 2020. Nowadays, approximately 60–70% of patients with this disorder have shown the lack of effectiveness and tolerability of the therapy with antidepressants. The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) are including pharmacogenetic information in the labeling of several antidepressants. The presence of this information represents the relevance of genetic polymorphisms in drug response. These pharmacogenetic studies have been based on the knowledge of genes involved in pharmacokinetic (CYP2D6, CYP2C19 and ABCB1) and pharmacodynamic (SLC6A4, HTR2A, BDNF, GNB3 and FKBP5) processes of antidepressant medications. The knowledge of the genotype of patients with MDD is an important tool for personalized therapy that can improve their clinical response to treatment. In this review, we highlight the most relevant genes involved in the metabolism of antidepressants (ADs) or the genes related to the presence of adverse reactions.


97. Ribeiro C., Martins P., Grazina M. Genotyping CYP2D6 by three different methods: advantages and disadvantages // Drug Metabolism and Personalized Therapy. 2017. Vol. 32, № 1. P. 33–37.

The three methods provide concordant results suggesting that any of these techniques is a reliable and sensitive method for genotyping CYP2D6. However, we would recommend the use of TaqMan® Drug Metabolism Assays, given the advantages concerning time spending, straightforwardness, reliability, and accuracy.


98. Rissmann R. et al. Concept-based learning of personalized prescribing // Br. J. Clin. Pharmacol. 2012. Vol. 74, № 4. P. 589–596.

The variability of drug response in different patients can be caused by various factors including age, change in renal function, co-medication and genotype. Traditionally, these personal variables are considered by clinicians prior to issuing a prescription. This paper provides an overview of a process to individualize prescribing for a patient with an emphasis on how to train (learning) clinicians in skillful rational prescribing. For this purpose the 6STEP methodology, a concept-based learning strategy to achieve a structured therapeutic plan, has been introduced. In contrast to older educational approaches which focused primarily on the drugs or the process of prescribing, the 6STEP is a patient-centred method resulting in individualized therapy. The six interlinked steps provide the (training) prescriber with a structured framework that facilitates a rationalized therapeutic decision by focusing on the individual patient parameters that influence drug response. Educational tools for rational prescribing involve understanding of basic and clinical pharmacological principles, practicing to write 6STEP therapeutic plans, learning from feedback sessions on these plans and actively obtaining up to date information on drugs and therapeutic standards from online resources.


99. Rodriguez-Antona C. The role of pharmacogenetics and pharmacogenomics in 21st-century medicine: state of the art and new challenges discussed in the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF) // Drug Metabolism and Personalized Therapy. 2015. Vol. 31, № 1. P. 1–2.

Recently, a very impressive achievement has been made regarding the availability of whole exomes and genomes, which are contributing to a much better understanding of human genetic variation and to the identification of variants associated with human diseases and complex phenotypes (including drug response). In this regard, the critical step has been the development of massively parallel sequencing technologies, which allow sequencing of an entire genome in less than a day in a cost-effective manner. This nextgeneration sequencing (NGS) technologies are the basis for international projects such as the 1000 Genomes Project and the Genotype-Tissue Expression project. NGS technologies have also contributed to the rapid increase of epi- genetic studies, adding one more layer to the genetic information.


100. Romaine S.P.R. et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy // Pharmacogenomics J. 2010. Vol. 10, № 1. P. 1–11.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide inter-individual variability in response to statin therapy, in terms of both lipid-lowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A>G and c.521T>C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.


101. Ron H.N. van Schaik New challenges for pharmacogenomics // Drug Metabolism and Drug Interactions. 2013. Vol. 28, № 4. P. 191–192.

This issue of Drug Metabolism and Drug Interactions (DMDI) follows the second conference of The European Society for Pharmacogenomics and Theranostics (ESPT) entitled “Pharmacogenomics: From Cell to Clinic” which took place from September 26–28, 2013


102. Rosskopf D., Michel M.C. Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine // Pharmacol. Rev. 2008. Vol. 60, № 4. P. 513–535.

Agonists and antagonists of G protein-coupled receptors are important drugs for the treatment of cardiovascular disease, but the therapeutic response of any given patient remains difficult to predict because of large interindividual variability. Among the factors potentially contributing to such variability, we have reviewed the evidence for a role of pharmacodynamic pharmacogenetics ( i.e., polymorphisms in the cognate receptors for such drugs as well as other proteins potentially modifying their action). Based upon the availability of data and the prevalence of use, we have focused on ligands at adrenergic and angiotensin II receptors ( including the indirectly acting angiotensin-converting enzyme inhibitors). The vast majority of gene polymorphisms reviewed here have shown only inconsistent effects on drug action, which does not make these polymorphisms useful genetic markers to predict treatment responses. We conclude that considerable additional research, partly involving other types of study than those available now, will be necessary to allow a definitive judgment whether pharmacodynamic pharmacogenetic markers are useful in an individualized approach to cardiovascular therapy. Moreover, we predict that even such additional research will result in only few cases where the promise of tailored treatment can be fulfilled; however, some of these few cases may be of major clinical relevance.


103. Russmann S., Jetter A., Kullak-Ublick G.A. Pharmacogenetics of Drug-Induced Liver Injury // Hepatology. 2010. Vol. 52, № 2. P. 748–761.

Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for


104. Rutter J.L. Symbiotic relationship of pharmacogenetics and drugs of abuse // Aaps Journal. 2006. Vol. 8, № 1. P. E174–E184.

Pharmacogenetics/pharmacogenomics is the study of how genetic variation affects pharmacology, the use of drugs to treat disease. When drug responses are predicted in advance, it is easier to tailor medications to different diseases and individuals. Pharmacogenetics provides the tools required to identify genetic predictors of probable drug response, drug efficacy, and drug-induced adverse events-identifications that would ideally precede treatment decisions. Drug abuse and addiction genetic data have advanced the field of pharmacogenetics in general. Although major findings have emerged, pharmacotherapy remains hindered by issues such as adverse events, time lag to drug efficacy, and heterogeneity of the disorders being treated. The sequencing of the human genome and high-throughput technologies are enabling pharmacogenetics to have greater influence on treatment approaches. This review highlights key studies and identifies important genes in drug abuse pharmacogenetics that provide a basis for better diagnosis and treatment of drug abuse disorders.


105. Sadee W. Gene-Gene-Environment Interactions Between Drugs, Transporters, Receptors, and Metabolizing Enzymes: Statins, SLCO1B1, and CYP3A4 as an Example // J. Pharm. Sci. 2013. Vol. 102, № 9. P. 2924–2929.

Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations.


106. Sams-Dodd F. Strategies to optimize the validity of disease models in the drug discovery process // Drug Discov. Today. 2006. Vol. 11, № 7–8. P. 355–363.

Models of human diseases are necessary for experimental research into the biological basis of disease and for the development of treatments. They have an enormous impact upon the success of biomedical research. However, in spite of this, a consistent system for evaluating, expressing and comparing the clinical validity of disease models is not available. The purpose of this paper is, therefore, to provide a, theoretical discussion of the concepts behind disease models and to develop a terminology and a framework to analyze and express the clinical validity of disease models.


107. Savonarola A. et al. Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy // Pharmacogenomics J. 2012. Vol. 12, № 4. P. 277–286.

The goal of cancer pharmacogenomics is to obtain benefit from personalized approaches of cancer treatment and prevention. Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and targets, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. Although a considerable amount of new targeted agents have been designed based on a finely understanding of molecular alterations in cancer, a wide gap between pharmacogenomic knowledge and clinical application still persists. This review focuses on the relevance of mutational analyses in predicting individual response to antitumor therapy, in order to improve the translational impact of genetic information on clinical practice.


108. Schmitz G., Langmann T. Pharmacogenomics of cholesterol-lowering therapy // Vasc. Pharmacol. 2006. Vol. 44, № 2. P. 75–89.

The prevention of cardiovascular disease is critically dependent oil lipid-lowering therapy, including 3 -hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors, bile acid resins, fibrates, and nicotinic acid. Although these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression. Significant progress has been made in the identification of common DNA sequence variations in genes influencing the pharmacokinetics and pharmacodynamics of statins and in disease-modifying genes relevant for coronary heart disease (CHD). Among the most promising candidate genes for pharmacogenomic analysis of statin therapy are HMG-CoA reductase as a direct target gene and other genes modulating lipid and lipoprotein homeostasis. Based on data from pharmacogenetic trials, a combined analysis of multiple genetic variants in several genes is more likely to give significant results than single gene studies in small cohorts. In the future, pharmacogenomic testing may allow risk stratification of patients to avoid serious side effects and enable clinicians to select lipid-lowering drugs with the highest efficacy resulting in the best response to therapy.


109. Schuck R.N., Grillo J.A. Pharmacogenomic Biomarkers: an FDA Perspective on Utilization in Biological Product Labeling // AAPS J. 2016. Vol. 18, № 3. P. 573–577.

Precision medicine promises to improve both the efficacy and safety of therapeutic products by better informing why some patients respond well to a drug, and some experience adverse reactions, while others do not. Pharmacogenomics is a key component of precision medicine and can be utilized to select optimal doses for patients, more precisely identify individuals who will respond to a treatment and avoid serious drug-related toxicities. Since pharmacogenomic biomarker information can help inform drug dosing, efficacy, and safety, pharmacogenomic data are critically reviewed by FDA staff to ensure effective use of pharmacogenomic strategies in drug development and appropriate incorporation into product labels. Pharmacogenomic information may be provided in drug or biological product labeling to inform health care providers about the impact of genotype on response to a drug through description of relevant genomic markers, functional effects of genomic variants, dosing recommendations based on genotype, and other applicable genomic information. The format and content of labeling for biologic drugs will generally follow that of small molecule drugs; however, there are notable differences in pharmacogenomic information that might be considered useful for biologic drugs in comparison to small molecule drugs. Furthermore, the rapid entry of biologic drugs for treatment of rare genetic diseases and molecularly defined subsets of common diseases will likely lead to increased use of pharmacogenomic information in biologic drug labels in the near future. In this review, we outline the general principles of therapeutic product labeling and discuss the utilization of pharmacogenomic information in biologic drug labels.


110. Shah R.R., Shah D.R. Personalized medicine: is it a pharmacogenetic mirage? // Br. J. Clin. Pharmacol. 2012. Vol. 74, № 4. P. 698–721.

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as the right drug at the right dose the first time. These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients.


111. Shastry B.S. Pharmacogenetics and the concept of individualized medicine // Pharmacogenomics J. 2006. Vol. 6, № 1. P. 16–21.

Adverse drug reaction in patients causes more than 2 million hospitalizations including 100 000 deaths per year in the United States. This adverse drug reaction could be due to multiple factors such as disease determinants, environmental and genetic factors. In order to improve the efficacy and safety and to understand the disposition and clinical consequences of drugs, two rapidly developing fields - pharmacogenetics (focus is on single genes) and pharmacogenomics (focus is on many genes) - have undertaken studies on the genetic personalization of drug response. This is because many drug responses appear to be genetically determined and the relationship between genotype and drug response may have a very valuable diagnostic value. Identification and characterization of a large number of genetic polymorphisms (biomarkers) in drug metabolizing enzymes and drug transporters in an ethnically diverse group of individuals may provide substantial knowledge about the mechanisms of inter-individual differences in drug response. However, progress in understanding complex diseases, its negative psychosocial consequences, violation of privacy or discrimination, associated cost and availability and its complexity (extensive geographic variations in genes) may become potential barriers in incorporating this pharmacogenetic data in risk assessment and treatment decisions. In addition, it requires increased enthusiasm and education in the clinical community and an understanding of pharmacogenetics itself by the lay public. Although individualized medications remain as a challenge for the future, the pharmacogenetic approach in drug development should be still continued. If it becomes a reality, it delivers benefits to improve public health and allow genetically subgroup diseases thereby avoiding adverse drug reactions (by knowing in advance who should be treated with what drug and how).


112. Shu W. et al. Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population // Acta Pharmacol. Sin. 2015. Vol. 36, № 5. P. 535–543.

The field of pharmacogenomics was initiated in the 1950s and began to thrive after the completion of the human genome project 10 years ago. Thus far, more than 100 drug labels and clinical guidelines referring to pharmacogenomic biomarkers have been published, and several key pharmacogenomic markers for either drug safety or efficacy have been identified and subsequently adopted in clinical practice as pre-treatment genetic tests. However, a tremendous variation of genetic backgrounds exists between different ethnic groups. The application of pharmacogenomics in the Chinese population is still a long way off, since the published guidelines issued by the organizations such as US Food and Drug Administration require further confirmation in the Chinese population. This review highlights important pharmacogenomic discoveries in the Chinese population and compares the Chinese population with other nations regarding the pharmacogenomics of five most commonly used drugs, ie, tacrolimus, cyclosporine A, warfarin, cyclophosphamide and azathioprine.


113. Sim S.C., Kacevska M., Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects // Pharmacogenomics J. 2013. Vol. 13, № 1. P. 1–11.

Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future.


114. Somogyi A.A., Barratt D.T., Coller J.K. Pharmacogenetics of opioids // Clin. Pharmacol. Ther. 2007. Vol. 81, № 3. P. 429–444.

Opioids; are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics; and dosage requirements. Single-nudeotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacoldnetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Serturner, a large number of opioid drugs beginning with modification of the 4,5-epoxyitnorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.


115. Stamp L. et al. The use of low dose methotrexate in rheumatoid arthritis - are we entering a new era of therapeutic drug monitoring and pharmacogenomics? // Biomed. Pharmacother. 2006. Vol. 60, № 10. P. 678–687.

Methotrexate (MTX) is one of the most commonly used medications in the treatment of rheumatoid arthritis (RA). It has proven efficacy as a sole agent as well as in combination with other disease modifying anti-rheumatic agents (DMARDs) including the newer biological agents. MTX is generally well tolerated although there are a number of potentially serious adverse effects. Of these, haematopoietic suppression, hepatotoxicity and pulmonary toxicity are the more severe and patients are therefore required to have appropriate monitoring while they remain on MTX. In the past, attempts at therapeutic drug monitoring using serum MTX concentrations have been unsuccessful. However, MTX is taken into red blood cells (RBC) where up to four glutamates are added to form MTX polyglutamates (MTXPG,). More recently it has been suggested that higher RBC MTXPG(3-5) concentrations may be associated with improved disease control. Genetic variations in enzymes involved in the uptake of MTX into cells and its metabolism are also being examined for their ability to predict drug response and potential for adverse events. While it is unlikely that a single genetic variant will predict efficacy or toxicity there is preliminary evidence that a "pharmacogenetic index" that takes into account the effects of multiple genetic variants maybe useful. Although in their infancy at present, both therapeutic drug monitoring using MTXPG concentrations and pharmacogenomics of MTX may prove useful in the future and are worthy of further investigation.


116. Stankov K., Sabo A., Mikov M. Pharmacogenetic Biomarkers as Tools for Pharmacoepidemiology of Severe Adverse Drug Reactions // Drug Dev. Res. 2013. Vol. 74, № 1. P. 1–14.

Preclinical Research The development of new genomic technologies has led to an exponential increase in the number of biomarkers for drug safety and efficacy. Pharmacogenomics has the potential to impact clinically relevant outcomes in drug dosing, efficacy, toxicity, and prediction of adverse drug reactions (ADRs). Genotype-based prescribing is anticipated to improve the overall efficacy rates and minimize ADRs, making personalized medicine a reality. Genome-wide association studies have been increasingly applied to pharmacogenetics. Severe ADRs are a major issue for drug therapy because they can cause serious disorders and can be life threatening. For severe ADRs, significant associations have been reported for drug-induced liver injury, statin-induced myopathy, increased risk of hemorrhagic complications of anticoagulant use, drug-induced torsade de pointes, drug-induced long QT, and severe cutaneous ADRs. This review summarizes the current position concerning the clinical and pharmacoepidemiological relevance of pharmacogenetic biomarkers in ADR prediction and prevention, with an emphasis on genetic risk factors and biomarkers for three specific severe ADRs.


117. Suarez-Kurtz G., Botton M.R. Pharmacogenomics of warfarin in populations of African descent // Br. J. Clin. Pharmacol. 2013. Vol. 75, № 2. P. 334–346.

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These Black populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G?>?A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are friendly enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity.


118. Sultana S.R., Roblin D., O’Connell D. Translational research in the pharmaceutical industry: from theory to reality // Drug Discov. Today. 2007. Vol. 12, № 9–10. P. 419–425.

Translational research is the collaboration between scientists and clinicians to identify novel targets and develop biomarkers that increase confidence in rationale and therefore help select the mechanisms that are most likely to lead to breakthrough therapies. Here, we describe examples of the utility of linked preclinical and clinical biomarkers to measure pharmacological effects, to estimate clinical dose range, to determine efficacy, and to determine differentiation compared with existing therapies. The use of pharmacogenomics to identify novel drug targets and define enriched patient subpopulations is also discussed. We illustrate how biomarkers and a deep understanding of disease biology are used to discover additional indications for licensed drugs.


119. Sychev D.A. et al. Evaluation of genotype-guided acenocoumarol dosing algorithms in Russian patients // Drug Metabolism and Personalized Therapy. 2017. Vol. 32, № 2. P. 109–114.

None of the existing algorithms could predict the ideal acenocoumarol dose in 50% of Russian patients. The Wolkanin-Bartnik algorithtm based on European population was the best-performing one with the highest correlation values (r=0.397), mean absolute error (MAE) 0.82 (±0.61). EU-PACT also managed to give an estimate within the ideal range in 43% of the cases. The two least accurate results were yielded by the Indian population-based algorithms. Among patients receiving amiodarone, algorithms by Schie and Tong proved to be the most effective with the MAE of 0.48±0.42 mg/day and 0.56±0.31 mg/day, respectively. Conclusions: Patient ethnicity and amiodarone intake are factors that must be considered when building future algorithms. Further research is required to find the perfect dosing formula of acenocoumarol maintenance doses in Russian patients.


120. Sychev D.A., Burashnikova I.S., Kazakov R.E. 1846G>A polymorphism of CYP2D6 gene and extrapyramidal side effects during antipsychotic therapy among Russians and Tatars: a pilot study // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 4. P. 205–212.

More pharmacogenetic studies are needed to assess the association of different polymorphisms, in particular of 1846G>A, and their effect on drug therapy. This will provide a better understanding of these links and hopefully lead to improved therapeutic approaches to eliminate, or at least ameliorate them, e.g. via personalized therapy. Considering ethnic genetic peculiarities, it is necessary to initiate well-designed research projects in different regions of Russia to exclude the influence of nongenetic factors in an attempt to clarify the role of genotyping indications in routine clinical practice.


121. Szalai C. et al. Asthma from a pharmacogenomic point of view // Br. J. Pharmacol. 2008. Vol. 153, № 8. P. 1602–1614.

Pharmacogenomics, a fascinating, emerging area of biomedical research is strongly influenced by growing availability of genomic databases, high-throughput genomic technologies, bioinformatic tools and artificial computational modelling approaches. One main area of pharmacogenomics is the discovery of new drugs and drug targets with molecular genetic, genomic or even bioinformatic methods; the other is the study of how genomic differences influence the variability in patients' responses to drugs. From a genetic point of view, asthma is multifactorial, which means that the susceptibility to the disease is determined by interactions between multiple genes, and involves important non-genetic factors such as the environment for their expression. In this review, we summarize collective evidence from linkage and association studies that have consistently reported suggestive linkage or association of asthma or its associated phenotypes to polymorphic markers and single nucleotide polymorphisms in selected chromosomes. Genes that have been found implicated in the disease are potential new drug targets and several pharmacological investigations are underway to utilize these new discoveries. Next, we will focus on the inter-individual variability in anti-asthmatic drug responses and review the recent results in this topic.


122. Tang J. et al. DNA methylation and personalized medicine // J. Clin. Pharm. Ther. 2014. Vol. 39, № 6. P. 621–627.

What is known and objectiveVariation in the expression of drug-response-related genes contributes significantly to interindividual differences in drug response. DNA methylation is one of the most common epigenetic modifications that control gene expression. DNA methylation may occur in genes encoding drug metabolizing enzymes (DMEs), drug transporters and drug targets, and can thereby alter the pharmacokinetics and pharmacodynamics of drugs. In this review, we discuss recent advances in pharmacoepigenetics with a focus on DNA methylation. MethodsThe literature search focusing on DNA methylation of drug-response-related genes and DNA methylation-related SNPs in pharmacogenomics was carried out using the PUBMED database and a combination of keywords including DNA methylation, drug response, DMEs, drug transporters, drug target and SNPs. Results and discussionAn extensive range of research has contributed to our understanding of how DNA methylation of drug-response-related genes alters their function. This is particularly well studied in cancer chemotherapy and drug resistance. The impact of polymorphisms of miRNAs in these processes requires further study. What is new and conclusionDNA methylation-related genetic variation is an increasingly recognized mechanism for altered drug-response and disease susceptibility. These new discoveries require assimilation into the practice of personalized medicine.


123. Thigpen J.L., Limdi N.A. Reversal of Oral Anticoagulation // Pharmacotherapy. 2013. Vol. 33, № 11. P. 1199–1213.

Although the use of dabigatran and rivaroxaban are increasing, data on the reversal of their effects are limited. The lack of reliable monitoring methods and specific reversal agents renders treatment strategies empirical, and as a result, treatment consists mainly of supportive measures. Therefore, we performed a systematic search of the PubMed database to find studies and reviews pertaining to oral anticoagulation reversal strategies. This review discusses current anticoagulation reversal recommendations for the oral anticoagulants warfarin, dabigatran, and rivaroxaban for patients at a heightened risk of bleeding, actively bleeding, or those in need of preprocedural anticoagulation reversal. We highlight the literature that shaped these recommendations and provide directions for future research to address knowledge gaps. Although reliable recommendations are available for anticoagulation reversal in patients treated with warfarin, guidance on the reversal of dabigatran and rivaroxaban is varied and equivocal. Given the increasing use of the newer agents, focused research is needed to identify effective reversal strategies and develop and implement an accurate method (assay) to guide reversal of the newer agents. Determining patient-specific factors that influence the effectiveness of reversal treatments and comparing the effectiveness of various treatment strategies are pertinent areas for future anticoagulation reversal research.


124. Thomas C., Moridani M. Interindividual variations in the efficacy and toxicity of vaccines // Toxicology. 2010. Vol. 278, № 2. P. 204–210.

A number of currently available vaccines have shown significant differences in the magnitude of immune responses and toxicity in individuals undergoing vaccination. A number of factors may be involved in the variations in immune responses, which include age, gender, race, amount and quality of the antigen, the dose administered and to some extent the route of administration, and genetics of immune system. Hence, it becomes imperative that researchers have tools such as genomics and proteomics at their disposal to predict which set of population is more likely to be non-responsive or develop toxicity to vaccines. In this article, we briefly review the influence of pharmacogenomics biomarkers on the efficacy and toxicity of some of the most frequently reported vaccines that showed a high rate of variability in response and toxicity towards hepatitis B, measles, mumps, rubella, influenza, and AIDS/HIV.


125. Thompson A. et al. Pharmacotherapy for alcohol dependence: A stratified approach // Pharmacol. Ther. 2015. Vol. 153. P. 10–24.

Alcohol dependence is a common disorder in many societies worldwide, and remains difficult to identify and treat. It is also a risk factor for many secondary non-communicable diseases. Pharmacotherapy is one available treatment option, but appears to be underutilised in practice. Major barriers to use of medications in this area include lack of clinical guidance and questionable efficacy. However, for each medication there appears to be a subpopulation that responds positively, and understanding the moderating factors to treatment efficacy is an important research goal. Thus, this review provides a narrative regarding potential stratification techniques in pharmacological treatment of alcohol dependence, with a specific focus on typologies and pharmacbgenetics. In addition, we discuss the basic background of stratified medicine and recent studies on genetic predisposition to alcohol dependence. A growing repository of data exists for both approved and non-approved pharmacotherapies, but failure to replicate findings, inadequate sample sizes, and insufficient funding has resulted in a translational gap. Implementing evidence-based stratified/personalised therapy and identifying new therapeutic agents may lead to improved clinical outcomes and reduced financial burden. Despite some promising findings to date, much work is still required.


126. Tsikouris J.P., Peeters M.J. Pharmacogenomics of renin angiotensin system inhibitors in coronary artery disease // Cardiovasc. Drugs Ther. 2007. Vol. 21, № 2. P. 121–132.

Renin Angiotensin System (RAS) inhibitors comprise some of the most commonly used medications in coronary artery disease (CAD) and its related syndromes. Unfortunately, significant inter-patient variability seems likely in response to these agents; of which, the influence of genetic determinants is of interest. This review summarizes the available RAS inhibitor pharmacogenomic studies which have evaluated RAS polymorphisms that either elucidate mechanism via surrogate endpoint measurements, or predict efficacy via clinical outcomes in CAD related syndromes.Regardless of the endpoint, none of the RAS genotypes conclusively predicts efficacy of RAS inhibitors. In fact, the results of the pharmacogenomic studies were often in direct conflict with one another. Varied results appear due to methodological limitations (e.g., inadequate study power, genotyping error, methods of endpoint measurement), study conceptualization (e.g., overestimating the contribution of polymorphism to disease, lack of haplotype approach), and differences between studies (e.g., genotype frequency, study subject characteristics, the specific medication and dose used). Thus investigators should consider the various methodological limitations to improve upon the current approach to RAS inhibitor pharmacogenomic research in the vast CAD population.


127. Turpeinen M., Zanger U.M. Cytochrome P450 2B6: function, genetics, and clinical relevance // Drug Metabolism and Drug Interactions. 2012. Vol. 27, № 4. P. 185–197.

Cytochrome P450 (CYP) 2B6 belongs to the set of important hepatic drug-metabolizing CYPs. It makes up roughly 3%–6% of total hepatic CYP content and metabolizes several pharmaceuticals including bupropion, efavirenz, cyclophosphamide, pethidine, ketamine and propofol. The enzyme is susceptible to drug-drug interactions by enzyme induction and inhibition. In addition to drugs, CYP2B6 is able to both detoxify and bioactivate a number of procarcinogens and environmental agents including pesticides and herbicides. There is an extensive interindividual variability in the expression of CYP2B6, which is in part explained by extensive genetic polymorphism. CYP2B6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs, numerous complex haplotypes and distinct ethnic and racial frequencies. This review summarizes the basic properties of CYP2B6 and the main characteristics of clinical relevance.


128. van Gool A.J., Henry B., Sprengers E.D. From biomarker strategies to biomarker activities and back // Drug Discov. Today. 2010. Vol. 15, № 3–4. P. 121–126.

The pharmaceutical industry must find ways to improve the unacceptably high attrition rate during drug development. Clearly, pharma has moved away from treat-and-see testing of new drugs in patients, with a strong current focus on generating translational biomarkers early in the research process to enable more predictive evaluation of drug action in clinical trials. Underlying such a translational medicine approach is the intensive search for and use of high-quality biomarkers indicative of successful drug target engagement, pharmacological effects, efficacy or safety. This review outlines our rational question-based drug development strategy in which biomarker data drive decisions on which drug candidates to progress to clinical testing.


129. VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF). “The role of pharmacogenetics and pharmacogenomics in the XXI century medicine: current state of the art and new challenges” // Drug Metabolism and Personalized Therapy. 2016. Vol. 31, № 1. P. eA1.

These abstracts have been reproduced directly from the material supplied by the authors, without editorial alteration by the staff of this Journal.


130. Visvikis-Siest S. et al. 8th Santorini Conference: Systems medicine and personalized health and therapy, Santorini, Greece, 3–5 October 2016 // Drug Metabolism and Personalized Therapy. 2017. Vol. 32, № 2. P. 119–127.

On conclusion, this conference raised major questions: – Can genetic screening help identify individuals at greatest risk for cardio-metabolic diseases and cancer? – What is the greatest clinical need with regard to diagnosis, prediction and patient stratification for these pathologies and how this is/can be addressed? Does a genetic risk score identify patients at highest risk and is its use justified in clinical practice? What are the challenges of the current clinical trials? – What about comorbidities with aging? – What is the impact of pharmacogenomics on: – Deliverance of more predictable responses to drug therapy – Minimization of the occurrence and severity of adverse drug reactions – Conduction of more cost-effective clinical trials – Drug discovery and the drug development process – Do the existing diagnostic tools answer the needs of pharmacogenomics?


131. Vo T.T., Gupta S.V. Role of Cytochrome P450 2B6 Pharmacogenomics in Determining Efavirenz-Mediated Central Nervous System Toxicity, Treatment Outcomes, and Dosage Adjustments in Patients with Human Immunodeficiency Virus Infection // Pharmacotherapy. 2016. Vol. 36, № 12. P. 1245–1254.

For treatment-naive patients with human immunodeficiency virus infection, efavirenz (EFV), together with tenofovir and emtricitabine, was once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system (CNS) toxicities from EFV prompted the U.S. Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and often the mainstay of treatment outside the United States because newer antiretroviral treatments are more expensive. CNS toxicity occurring with the recommended standard dose of EFV remains a challenge and may in part be attributable to polymorphisms in cytochrome P450 (CYP) 2B6, the enzyme involved in the major metabolic pathway for converting EFV to inactive metabolites. Functionally deficient alleles of CYP2B6 such as CYP2B6*6, *18, and *22 may be responsible for significantly higher therapeutic concentrations of EFV at a standard dose of 600 mg/day. We conducted a thorough review of the reported studies to elucidate the relationship between polymorphisms in CYP2B6 with adverse events and treatment response, including virologic suppression, immunologic response, resistance, and discontinuation of treatment. Compelling evidence exists to support the case for CYP2B6 genotype-guided EFV therapy while acknowledging the need for prospective controlled clinical trials to evaluate its clinical utility.


132. Wang Y. et al. Delivering systems pharmacogenomics towards precision medicine through mathematics // Adv. Drug Deliv. Rev. 2013. Vol. 65, № 7. P. 905–911.

The latest developments of pharmacology in the post-genomic era foster the emergence of new biomarkers that represent the future of drug targets. To identify these biomarkers, we need a major shift from traditional genomic analyses alone, moving the focus towards systems approaches to elucidating genetic variation in biochemical pathways of drug response. Is there any general model that can accelerate this shift via a merger of systems biology and pharmacogenomics? Here we describe a statistical framework for mapping dynamic genes that affect drug response by incorporating its pharmacokinetic and pharmacodynamic pathways. This framework is expanded to shed light on the mechanistic and therapeutic differences of drug response based on pharmacogenetic information, coupled with genomic, proteomic and metabolic data, allowing novel therapeutic targets and genetic biomarkers to be characterized and utilized for drug discovery.


133. Wang Z. et al. Statistical resolution of missing longitudinal data in clinical pharmacogenomics // Adv. Drug Deliv. Rev. 2013. Vol. 65, № 7. P. 980–986.

Clinical pharmacogenomics, integrating genomic information with clinical practices to facilitate the prediction of drug response, has recently emerged as a vital area of public health. In clinical trials, phenotypic data on drug response are often longitudinal, with some patients dropping out early due to physiological or other unpredictable reasons. The genetic analysis of such missing longitudinal data presents a significant challenge in clinical pharmacogenomics. We develop a statistical algorithm for detecting haplotypes that control longitudinal responses subject to non-ignorable dropout. The model was derived by incorporating the selection model into a dynamic model - functional mapping, aimed to discover genetic variants that contribute to phenotypic variation in longitudinal traits. The selection models is a statistical approach for analyzing missing longitudinal data by assuming that dropout depends on the outcome of drug response. The model derived can jointly characterize the genetic control of longitudinal responses and dropout events. Simulation studies were performed to investigate the statistical properties of the model and validate its practical usefulness. The model will find its implications for clinical pharmacogenomics toward personalized medicine.


134. Wang Z. et al. Stochastic modeling of systems mapping in pharmacogenomics // Adv. Drug Deliv. Rev. 2013. Vol. 65, № 7. P. 912–917.

As a basis of personalized medicine, pharmacogenetics and pharmacogenomics that aim to study the genetic architecture of drug response critically rely on dynamic modeling of how a drug is absorbed and transported to target tissues where the drug interacts with body molecules to produce drug effects. Systems mapping provides a general framework for integrating systems pharmacology and pharmacogenomics through robust ordinary differential equations. In this chapter, we extend systems mapping to more complex and more heterogeneous structure of drug response by implementing stochastic differential equations (SDE). We argue that SDE-implemented systems mapping provides a computational too) for pharmacogenetic or pharmacogenomic research towards personalized medicine.


135. Westbrook K., Stearns V. Pharmacogenomics of breast cancer therapy: An update // Pharmacol. Ther. 2013. Vol. 139, № 1. P. 1–11.

Clinical and histopathologic characteristics of breast cancer have long played an important role in treatment decision-making. Well-recognized prognostic factors include tumor size, node status, presence or absence of metastases, tumor grade, and hormone receptor expression. High tumor grade, presence of hormone receptors, and HER2-positivity are a few predictive markers of response to chemotherapy, endocrine manipulations, and anti-HER2 agents, respectively. However, there is much heterogeneity of outcomes in patients with similar clinical and pathologic features despite equivalent treatment regimens. Some of the differences in response to specific therapies can be attributed to somatic tumor characteristics, such as degree of estrogen receptor expression and HER2 status. In recent years, there has been great interest in evaluating the role that pharmacogenetics/pharmacogenomics, or variations in germline DNA, play in alteration of drug metabolism and activity, thus leading to disparate outcomes among patients with similar tumor characteristics. The utility of these variations in treatment decision-making remains debated. Here we review the data available to date on genomic variants that may influence response to drugs commonly used to treat breast cancer. While none of the variants reported to date have demonstrated clinical utility, ongoing prospective studies and increasing understanding of pharmacogenetics will allow us to better predict risk of toxicity or likelihood of response to specific treatments and to provide a more personalized therapy.


136. Wilke R.A. High-density lipoprotein (HDL) cholesterol: leveraging practice-based biobank cohorts to characterize clinical and genetic predictors of treatment outcome // Pharmacogenomics J. 2011. Vol. 11, № 3. P. 162–173.

Over the past decade, large multicenter trials have unequivocally demonstrated that decreasing low-density lipoprotein (LDL) cholesterol can reduce both primary and secondary cardiovascular events in patients at risk. However, even in the context of maximal LDL lowering, there remains considerable residual cardiovascular risk. Some of this risk can be attributed to variability in high-density lipoprotein (HDL) cholesterol. As such, there is tremendous interest in defining determinants of HDL homeostasis. Risk prediction models are being constructed based upon (1) clinical contributors, (2) known molecular determinants and (3) the genetic architecture underlying HDL cholesterol levels. To date, however, no single resource has combined these factors within the context of a practice-based data set. Recently, a number of academic medical centers have begun constructing DNA biobanks linked to secure encrypted versions of their respective electronic medical record. As these biobanks combine resources, the clinical community is in a position to characterize lipid-related treatment outcome on an unprecedented scale.


137. Wing K. et al. Development of predictive genetic tests for improving the safety of new medicines: the utilization of routinely collected electronic health records // Drug Discov. Today. 2014. Vol. 19, № 4. P. 361–366.

Serious adverse drug reactions are an important cause of hospitalization and can result in the withdrawal of licensed drugs. Genetic variation has been shown to influence adverse drug reaction susceptibility, and predictive genetic tests have been developed for a limited number of adverse drug reactions. The identification of patients with adverse drug reactions, obtaining samples for genetic analysis and rigorous evaluation of clinical test effectiveness represent significant challenges to predictive genetic test development. Using the example of serious drug-induced liver injury, we illustrate how a database of routinely collected electronic health records (EHRs) could be used to overcome these barriers by facilitating rapid recruitment to genome-wide association studies and supporting efficient randomized controlled trials of predictive genetic test effectiveness.


138. Wolf S.J. et al. An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics // Pharmacogenomics J. 2011. Vol. 11, № 5. P. 315–325.

The human ABCB1 protein, (P-glycoprotein or MDR1) is a membrane-bound glycoprotein that harnesses the energy of ATP hydrolysis to drive the unidirectional transport of substrates from the cytoplasm to the extracellular space. As a large range of therapeutic agents are known substrates of ABCB1 protein, its role in the onset of multidrug resistance has been the focus of much research. This role has been of particular interest in the field of pharmacogenomics where genetic variation within the ABCB1 gene, particularly in the form of single nucleotide polymorphisms (SNPs), is believed to contribute to inter-individual variation in ABCB1 function and drug response. In this review we provide an update on the influence of coding region SNPs within the ABCB1 gene on drug pharmacokinetics. By utilizing the crystal structure of the mouse ABCB1 homolog (Abcb1a), which is 87% homologous to the human sequence, we accompany this discussion with a graphical representation of residue location for amino acids corresponding to human ABCB1 coding region SNPs. Also, an assessment of residue conservation, which is calculated following multiple sequence alignment of 11 confirmed sequences of ABCB1 homologs, is presented and discussed. Superimposing a 'heat map' of residue homology to the Abcb1a crystal structure has permitted additional insights into both the conservation of individual residues and the conservation of their immediate surroundings. Such graphical representation of residue location and conservation supplements this update of ABCB1 pharmacogenetics to help clarify the often confounding reports on the influence of ABCB1 polymorphisms on drug pharmacokinetics and response.


139. Wu R. et al. A conceptual framework for pharmacodynamic genome-wide association studies in pharmacogenomics // Drug Discov. Today. 2011. Vol. 16, № 19–20. P. 884–890.

Genome-wide association studies (GWAS) have emerged as a powerful tool to identify loci that affect drug response or susceptibility to adverse drug reactions. However, current GWAS based on a simple analysis of associations between genotype and phenotype ignores the biochemical reactions of drug response, thus limiting the scope of inference about its genetic architecture. To facilitate the inference of GWAS in pharmacogenomics, we sought to undertake the mathematical integration of the pharmacodynamic (PD) process of drug reactions through computational models. By estimating and testing the genetic control of PD and pharmacokinetic (PK) parameters, this mechanistic approach does not only enhance the biological and clinical relevance of significant genetic associations, but also improve the statistical power and robustness of gene detection. This report discusses the general principle and development of PDs-based GWAS, highlights the practical use of this approach in addressing various pharmacogenomic problems, and suggests that this approach will be an important method to study the genetic architecture of drug responses or reactions.


140. Xie H.-G. et al. Individual variability in the disposition of and response to clopidogrel: Pharmacogenomics and beyond // Pharmacol. Ther. 2011. Vol. 129, № 3. P. 267–289.

The widespread use of clopidogrel alone or in combination with aspirin has significantly benefited patients with acute coronary syndrome who are managed medically or by percutaneous coronary intervention and stent implantation, greatly improving their survival. Emerging data have documented that the clopidogrel response may vary from person to person and even from disease to disease, and that genetic and nongenetic factors contribute to that variability. Genetic polymorphisms affecting clopidogrel metabolic bioactivation and platelet function may be responsible, each exerting a small effect CYP2C19 *2, *3 and *17, CYP2C9 *2 and *3, MDR1*2, and functional variants in the genes encoding platelet membrane receptors and intracellular signaling proteins are involved, and other genetic factors remain to be identified. In addition, nongenetic factors may be influential covariates, such as ethnicity, gender, age, body weight, co-existing diseases, drug drug interactions, and other factors to be determined. Each piece of the puzzle would be useful to bridge and delineate identified knowledge gaps and to determine future research needs for the risk prediction of fatal complications associated with inadequate clopidogrel therapy in patient care.


141. Yang Y., Peter I., Scott S.A. Pharmacogenetics in Jewish populations // Drug Metabolism and Drug Interactions. 2014. Vol. 29, № 4. P. 221–233.

Spanning over 2000 years, the Jewish population has a long history of migration, population bottlenecks, expansions, and geographical isolation, which has resulted in a unique genetic architecture among the Jewish people. As such, many Mendelian disease genes and founder mutations for autosomal recessive diseases have been discovered in several Jewish groups, which have prompted recent genomic studies in the Jewish population on common disease susceptibility and other complex traits. Although few studies on the genetic determinants of drug response variability have been reported in the Jewish population, a number of unique pharmacogenetic variants have been discovered that are more common in Jewish populations than in other major racial groups. Notable examples identified in the Ashkenazi Jewish (AJ) population include the vitamin K epoxide reductase complex subunit 1 (VKORC1) c.106G>T (p.D36Y) variant associated with high warfarin dosing requirements and the recently reported cytochrome P450 2C19 (CYP2C19) allele, CYP2C19*4B, that harbors both loss-of-function [*4 (c.1A>G)] and increased-function [*17 (c.-806C>T)] variants on the same haplotype. These data are encouraging in that like other ethnicities and subpopulations, the Jewish population likely harbors numerous pharmacogenetic variants that are uncommon or absent in other larger racial groups and ethnicities. In addition to unique variants, common multi-ethnic variants in key drug metabolism genes (e.g., ABCB1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, NAT2) have also been detected in the AJ and other Jewish groups. This review aims to summarize the currently available pharmacogenetics literature and discuss future directions for related research with this unique population.


142. Yao L. et al. Electronic health records: Implications for drug discovery // Drug Discov. Today. 2011. Vol. 16, № 13–14. P. 594–599.

Electronic health records (EHRs) have increased in popularity in many countries. Pushed by legal mandates, EHR systems have seen substantial progress recently, including increasing adoption of standards, improved medical vocabularies and enhancements in technical infrastructure for data sharing across healthcare providers. Although the progress is directly beneficial to patient care in a hospital or clinical setting, it can also aid drug discovery. In this article, we review three specific applications of EHRs in a drug discovery context: finding novel relationships between diseases, re-evaluating drug usage and discovering phenotype-genotype associations. We believe that in the near future EHR systems and related databases will impact significantly how we discover and develop safe and efficacious medicines.


143. Yiannakopoulou E. Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications // Eur. J. Clin. Pharmacol. 2013. Vol. 69, № 7. P. 1369–1373.

Pharmacogenomics investigates interindividual genetic variability in the DNA sequence of drug targets, drug-metabolizing enzymes or disease genes, RNA expression, or protein translation of genes affecting drug response and drug safety. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications with well-documented variation in patient response in terms of efficacy and safety. This variation may in part be explained by pharmacogenomics. In this paper I review data on the pharmacogenomics of aspirin and other NSAIDs focusing on clinical implications. Existing scientific evidence supports the pharmacogenomic basis of interindividual variation in treatment response to aspirin and NSAIDs, with clinical implications for antiplatelet action, cancer chemoprevention, and drug safety. However, further research efforts are needed before knowledge on the pharmacogenomics of aspirin and NSAIDs can be implemented in clinical practice. The outcome of these research efforts would be anticipated to have added value for both science and society, contributing to the enhanced efficacy and safety of these agents through patient selection.


144. Yiannakopoulou E.C. Pharmacogenomics of phase II metabolizing enzymes and drug transporters: clinical implications // Pharmacogenomics J. 2013. Vol. 13, № 2. P. 105–109.

The clinical impact of pharmacogenomics remains a hot topic of current research efforts. Although pharmacogenomics of phase I metabolizing enzymes seems to have been well studied, knowledge on the clinical impact of genetic variability of phase II metabolizing enzymes and drug transporters is more limited. This paper reviews data on the pharmacogenomics of phase II metabolizing enzymes as well as of ATP binding cassette transporters and of solute carrier transporters focusing on clinical implications for drug efficacy and drug toxicity. The clinical impact of some of these polymorphisms has been well defined i.e. the association between polymorphisms of organic anion transporter polypeptides and statin induced myopathy. However, as the same drug may be substrate for different enzymes and different transporters, it is difficult to elucidate the impact of each polymorphism. Investigating the impact of multiple polymorphisms might be more clinically meaningful, although methodologically challenging.


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