Role of OATP transporters in the disposition of drugs

During recent years, it has become increasingly recognized that drug transporters play important roles in drug absorption and disposition. Organic anion transporting polypeptides (OATPs) are membrane transporters critically involved in the cellular uptake of drugs in tissues important for pharmacokinetics, such as the intestine, liver and kidneys. Recent advances in the pharmacogenomics of OATP1B1 have revealed that OATP transporters can play important roles in explaining interindividual variability in drug pharmacokinetics, and thus contribute to interindividual as well as interethnic variability in drug response. This article will provide an up-to-date review of human OATPs and their substrates, and a current compilation of their DNA sequence variations.     

Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms

Organic anion transporting polypeptides (OATPs, gene family: SLC21/SLCO) mediate the uptake of a broad range of substrates including several widely prescribed drugs into cells. Drug substrates for members of the human OATP family include HMG-CoA-reductase inhibitors (statins), antibiotics, anticancer agents, and cardiac glycosides. OATPs are expressed in a variety of different tissues including brain, intestine, liver, and kidney, suggesting that these uptake transporters are important for drug absorption, distribution, and excretion. Because of their wide tissue distribution and broad substrate spectrum, altered transport kinetics, for example, due to drug-drug interactions or due to the functional consequences of genetic variations (polymorphisms), can contribute to the interindividual variability of drug effects. Therefore, the molecular characteristics of human OATP family members, the role of human OATPs in drug-drug interactions, and the in vitro analysis of the functional consequences of genetic variations in SLCO genes encoding OATP proteins are the focus of this chapter.     

Pharmacogenomics of human OATP transporters

Organic anion transporting polypeptides (OATPs) mediate the uptake of a broad range of compounds into cells. Substrates for members of the OATP family include bile salts, hormones, and steroid conjugates as well as drugs like the HMG-CoA-reductase inhibitors (statins), cardiac glycosides, anticancer agents like methotrexate, and antibiotics like rifampicin. OATPs are expressed in a variety of different tissues, including intestine, liver, kidney, and brain, suggesting that they play a critical role in drug absorption, distribution, and excretion. The identification and functional characterisation of naturally occurring variations in genes encoding human OATP (SLCO) family members is in the focus of transporter research. As a result of their broad substrate spectrum and their wide tissue distribution, altered transport characteristics or protein localisation can contribute significantly to interindividual variations of drug effects. The analysis of the consequences of genetic variations in genes encoding transport proteins may, therefore, contribute to a better understanding of interindividual differences in drug effects and to individualise treatment regimens with drugs that are substrates for human OATP proteins. In this review, we summarise the current knowledge on genetic variations in transporter genes encoding human OATP family members and their functional consequences analysed by in vitro and in vivo studies.     

Epigenetic-dependent regulation of drug transport and metabolism: an update

The pharmacokinetics of a drug are subject to large interindividual variability, which can result in lack of response or adverse drug reactions. In addition to genetic polymorphisms and drug interactions, key genes involved in the metabolism and transport of drugs are demonstrated to have epigenetic influences that can potentially affect interindividual variability in drug response. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug action and resistance, particularly in cancer. However, the epigenetic and ncRNA-dependent regulation of these genes, as well as the pharmacological consequences, is in need of greater attention. In the current review we provide an update of epigenetic and ncRNA-dependent regulation of ADME genes.     

Pharmacogenetics of statins therapy

Cardiovascular disease has become the global leading cause of death worldwide, representing the most frequent cause of morbidity and mortality in the developed world. Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Meta-analyses from several primary and secondary intervention studies have clearly shown that cholesterol-lowering medication, significantly reduces cardiovascular events, mortality, and morbidity, but considerable interindividual variation exists in response to statin therapy. Pharmacogenomics can provide important insights into statins therapy through elucidation of the genetic (or genomic) contribution to variable response for these drugs. The search for genetic polymorphisms may enable us to identify novel determinants of drug responsiveness by means of the study of three candidate genes groups: (1) genes encoding proteins involved in metabolism or drug transport, or both, that influence drug pharmacokinetics; (2) genes encoding proteins involved in mechanism of action and/or metabolic pathways on which drugs operate (that influence pharmacodynamics); (3) genes encoding proteins involved in the underlying disease condition or intermediate phenotype. This review briefly summarizes the recent pharmacogenomic and pharmacogenetic patents and the potential contributions of genetic variations in candidate genes related to lipid and lipoprotein metabolism and statins efficacy.     

Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy

Most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences result in part from polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and/or drug targets (eg, receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis of differences in drug efficacy and toxicity, using genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms, such as thiopurine S-methyltransferase (TPMT), monogenic traits have a marked effect on the pharmacokinetics of medications, such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (eg, 5-10% of the standard thiopurine dose). This review uses the TPMT polymorphism and thiopurine therapy (eg, azathioprine, mercaptopurine) to illustrate the potential of pharmacogenomics to elucidate genetic determinants of drug response, and optimize the selection of drug therapy for individual patients.     

Therapeutic failure: importance of genes?

Drug management can be a difficult task in certain situations because of the variable response observed from one patient to another. Genetic factors affecting the pharmacokinetics and pharmacodynamics of drug reactions could explain the interindividual variability in drug response. Pharmacogenetic analysis provides insight into the molecular mechanisms involved in drug response, with the ultimate goal of achieving optimal drug efficacy and safety. Numerous polymorphisms have been described in genes encoding drug-metabolising enzymes, transporters, and receptors. For some drugs, the impact on drug bioavailability and effect has been elucidated. We review here the molecular basis of interindividual variation in drug response and the methods used to identify individual risk of drug failure or toxicity. Clinical applications, concerning enzymes metabolising drugs (cytochrome P4502D6, thiopurine S-methyltransferase and N-acetyltransferase) provide an illustrative demonstration of the usefulness of pharmacogenetic tests in improving patient management. Clinical validation of these tests and new technologies (real-time PCR, DNA chips) should, in the future promote pharmacogenetics in clinical practice and may be lead to more individualized drug therapy.     

Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.     

Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences

To clarify the considerable interindividual variability in the pharmacokinetics, efficacy, and toxicity of drugs, genetic polymorphism of drug transporters has attracted interest because these transporters play important roles in the gastrointestinal absorption, biliary and renal elimination, and distribution to target sites of their substrates. Of the over 325 members of the solute carrier superfamily, this review focuses on the molecular features, expressional regulation, and genetic polymorphisms of the organic cation transporter (OCT) family, and the pharmacokinetic or pharmacodynamic consequences for organic cationic drugs. Although the clinical significance is still unclear, many studies have reported the importance of OCTs in the tissue distribution and elimination of their substrates in vitro and in vivo, and the impact of functional non-synonymous single nucleotide polymorphisms or differential expression levels of OCTs on the large interindividual variation in the pharmacokinetics and response of organic cationic drugs such as metformin, imatinib, and cisplatin.     

帕金森病药物治疗的遗传药理学研究进展

帕金森病是中老龄人中常见的神经退行性疾病,主要以拟多巴胺类药物治疗为主,但药物反应个体差异较大。与多巴胺代谢相关基因的遗传变异是导致药物反应个体差异的重要原因之一。目前国内研究主要集中在遗传多态性与帕金森病易感性之间的关系方面,而对帕金森病治疗的遗传药理学研究相对较少。该文对多巴胺转运体、多巴胺代谢酶和作用的受体等相关基因的遗传多态性与帕金森病治疗反应个体差异相关性方面的研究进行了一个较为全面的阐述。     

Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.     

How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.     

Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs

There is convincing evidence that many organic anion transporting polypeptide (OATP) transporters influence the pharmacokinetics and pharmacological efficacy of their substrate drugs. Each OATP family member has a unique combination of tissue distribution, substrate specificity and mechanisms of gene expression. Among them, OATP1B1, OATP1B3 and OATP2B1 have been considered as critical molecular determinants of the pharmacokinetics of a variety of clinically important drugs. Liver-specific expression of OATP1B1 and OATP1B3 contributes to the hepatic uptake of drugs from the portal vein, and OATP2B1 may alter their intestinal absorption as well as hepatic extraction. Accordingly, changes in function and expression of these three OATPs owing to genetic polymorphisms may lead to altered pharmacological effects, including decreased drug efficacy and increased risk of adverse effects. Association of genetic polymorphisms in OATP genes with alterations in the pharmacokinetic properties of their substrate drugs has been reported; however, there still exists a degree of discordance between the reported outcomes in different clinical settings. For better understanding of the clinical relevance of genetic polymorphisms of OATP1B1, OATP1B3 and OATP2B1, the present review focuses on the association of the genotypes of these OATPs with in vitro activity changes and in vivo clinical outcomes of substrate drugs.     

Genetic basis of drug metabolism.

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed. Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.     

表观遗传药理学与药物反应个体差异

随着遗传药理学和药物基因组学的不断发展,人们逐渐发现药物反应的个体差异不能够完全用基因的遗传多态性来解释。表观遗传药理学应运而生,从表观遗传学的角度来研究遗传因素与药物治疗的关系。许多药物代谢酶、转运体、转录因子、药物靶点以及核受体的编码基因均受到表观遗传学因素的调控,为临床上药物反应产生个体差异以及化疗耐药等提供了新的解释。本综述总结了近年来表观遗传药理学领域的最新进展。     

铂类药物神经毒性的药物基因组学研究进展

铂类药物广泛的应用于肺癌、大肠癌、卵巢癌、乳腺癌等多种癌症的治疗。然而,铂类药物的疗效往往由于严重的毒副反应,尤其是神经毒性而受到限制。铂类药物的神经毒性存在较大的个体性差异,其药物代谢相关基因的遗传变异是导致神经毒性个体差异的重要原因之一。本文就铂类药物转运体、药物代谢酶和DNA修复酶等相关基因的遗传多态性与铂类药物神经毒性之间的相关性作一综述。     

抗癫痫药的群体药代动力学与CYP450基因多态性的研究进展

抗癫痫药代谢的个体差异较大，需要个体化用药。群体药代动力学的研究是设计个体化治疗方案的有效方法。国内外对新老抗癫痫药的群体药代动力学进行了广泛研究，分析了一般生物学特征对药物代谢的影响。CYP450基因多态性是影响抗癫痫药物代谢的主要遗传因素，是个体差异的重要原因。目前，已有研究将CYP450基因多态性的因素引入群体药代动力学的模型，将其对抗癫痫药物代谢的影响进行了量化，并且，可以依据不同的基因型选择不同的初始剂量，促进个体化治疗，取得了新的进展。但是，有项研究提示基因多态性对群体药代动力学（PPK）参数的影响没有统计学意义。因此，目前的结论尚不完全一致，需要进一步研究。     

Pharmacogenetics approach to therapeutics

1. Pharmacogenetics refers to the study of genetically controlled variations in drug response. Functional variants caused by single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolising enzymes, transporters, ion channels and drug receptors have been known to be associated with interindividual and interethnic variation in drug response. Genetic variations in these genes play a role in influencing the efficacy and toxicity of medications. 2. Rapid, precise and cost-effective high-throughput technological platforms are essential for performing large-scale mutational analysis of genetic markers involved in the aetiology of variable responses to drug therapy. 3. The application of a pharmacogenetics approach to therapeutics in general clinical practice is still far from being achieved today owing to various constraints, such as limited accessibility of technology, inadequate knowledge, ambiguity of the role of variants and ethical concerns. 4. Drug actions are determined by the interplay of several genes encoding different proteins involved in various biochemical pathways. With rapidly emerging SNP discovery technological platforms and widespread knowledge on the role of SNPs in disease susceptibility and variability in drug response, the pharmacogenetics approach to therapeutics is anticipated to take off in the not-too-distant future. This will present profound clinical, economic and social implications for health care.     

Impact of Genetic Polymorphisms on the Efficacy of HMG-CoA Reductase Inhibitors

Although pharmacologic treatment for cholesterol reduction represents an advance in cardiovascular and atherosclerosis treatment, the benefits of such therapy are still limited because of interindividual variability in the response to these drugs. Disease severity, treatment adherence, physiologic conditions, biologic conditions, and the patient's genetic profile could be cited as important factors in the evaluation of interindividual variability. In regard to the latter consideration, three large groups of genes could be investigated: (i) genes that code for proteins involved in metabolism and/or drug transport, thereby influencing the pharmacokinetics of these compounds; (ii) genes that code for proteins involved in the mechanism of action and/or in the metabolic pathway of drug action, and which therefore influence pharmacodynamics; and (iii) genes that code for proteins involved in direct development of the disease or in intermediate phenotypes. In this review we discuss pharmacogenetic studies of the HMG-CoA reductase inhibitors (statins) and the implications of pharmacogenetic considerations for predicting treatment efficacy and reducing the adverse effects of these drugs. Once new studies have been performed and most of the genetic variability associated with drug action has been revealed, the great challenge will be to apply this knowledge in clinical medicine.     

Pharmacogenetics of antiparkinsonian drug treatment: a systematic review

Pharmacotherapy is the mainstay in the treatment of Parkinson's disease and the armamentarium of drugs available for the therapy of this disease is still expanding. Anti-Parkinson's disease drugs are effective in reducing the physical symptoms, such as hypokinesia, bradykinesia, rigidity and tremor. However, there is a large interindividual variability in response to anti-Parkinson's disease drugs with respect to both drug efficacy and toxicity. It is thought that genetic variability in genes encoding drug-metabolizing enzymes, drug receptors and proteins involved in pathway signaling is an important factor in determining interindividual variability in drug response. Pharmacogenetics aims at identifying genetic markers associated with drug response. Ideally, knowledge of these genetic markers will enable us to predict an individual's drug response in terms of both efficacy and toxicity. The role of pharmacogenetics in the treatment of Parkinson's disease is relatively unexplored. Therefore, we aim to present a systematic review of the published pharmacogenetic studies in Parkinson's disease and to describe polymorphic genes of interest for future research.