Genetic polymorphisms in placental transporters: implications for fetal drug exposure to oral antidiabetic agents

INTRODUCTION: The prevalence of diabetes among women of childbearing age is increasing. This will inevitably increase the number of pregnancies complicated by diabetes. The management of diabetes mellitus often necessitates the use of oral antidiabetic drugs including biguanides, sulfonylureas, metiglinide analogs and thiazolidinediones. However, a significant concern with the use of these agents in pregnancy is the potential for developmental toxicity. Various antidiabetic drugs have been identified as substrates for transporters present in the syncytiotrophoblast. Therefore, the extent of transfer and fetal exposure to oral antidiabetic drugs used in pregnancy may be altered by polymorphisms in genes encoding these transport proteins. AREAS COVERED: This review covers current research examining genetic polymorphisms in transporters expressed in the syncytiotrophoblast and evidence supporting the involvement of these transporters in the transport of oral antidiabetic agents. The aim is to provide insight into how the transfer of antidiabetic drugs across the placental trophoblast may be altered by polymorphisms in drug transporters. EXPERT OPINION: There is a paucity of studies examining the influence of polymorphisms on transporter activity in the placenta and how the transfer of oral antidiabetics may be altered. Further research employing in vivo models is required to allow for the prediction of the potential consequences of polymorphisms on placental transporter expression and function.     

Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.     

Impact of drug transporter studies on drug discovery and development

Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.     

有机阴离子转运多肽1B1的遗传药理学进展

人体存在多种类型的药物转运体,对于药物的吸收、分布和排泄起重要作用。参与药物跨膜转运的转运体功能受影响,将可能导致诸多临床药物的疗效、毒副作用甚至药物相互作用的发生。在各种影响因素中,遗传多态性所起的作用最为重要,可导致基因表达和蛋白功能发生改变。目前,阐明转运体基因的多态性以及基因型与表型之间的相互关系已成为应用遗传信息指导临床个体化用药的必要步骤。本文就肝脏有机阴离子转运多肽1B1（OATP1B1[OATP-C],编码基因SLCO1B1）基因多态性对药代动力学和药效动力学的影响及其临床意义等方面的进展作一综述。     

Human membrane transporter database: A web-accessible relational database for drug transport studies and pharmacogenomics

The human genome contains numerous genes that encode membrane transporters and related proteins. For drug discovery, development, and targeting, one needs to know which transporters play a role in drug disposition and effects. Moreover, genetic polymorphisms in human membrane transporters may contribute to interindividual differences in the response to drugs. Pharmacogenetics, and, on a genome-wide basis, pharmacogenomics, address the effect of genetic variants on an individual's response to drugs and xenobiotics. However, our knowledge of the relevant transporters is limited at present. To facilitate the study of drug transporters on a broad scale, including the use of microarray technology, we have constructed a human membrane transporter database (HMTD). Even though it is still largely incomplete, the database contains information on more than 250 human membrane transporters, such as sequence, gene family, structure, function, substrate, tissue distribution, and genetic disorders associated with transporter polymorphisms. Readers are invited to submit additional data. Implemented as a relational database, HMTD supports complex biological queries. Accessible through a Web browser user interface via Common Gateway Interface (CGI) and Java Database Connection (JDBC) (http://128.218.208.23/transporter/trans.html), HMTD also provides useful links and references, allowing interactive searching and downloading of data. Taking advantage of the features of an electronic journal, this paper serves as an interactive tutorial for using the database, which we expect to develop into a research tool.     

Genetic polymorphisms in diabetes: influence on therapy with oral antidiabetics

Due to new genetic insights, etiologic classification of diabetes is under constant scrutiny. Hundreds, or even thousands, of genes are linked with type 2 diabetes. Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to be predisposed to type 2 diabetes mellitus across many large studies. Individually, each of these polymorphisms is only moderately predisposed to type 2 diabetes. On the other hand, monogenic forms of diabetes such as MODY and neonatal diabetes are characterized by unique clinical features and the possibility of applying a tailored treatment.Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of a number of medications. Mutations in genes important in drug absorption, distribution, metabolism and excretion (ADME) play a critical role in pharmacogenetics of diabetes.There are currently five major classes of oral pharmacological agents available to treat type 2 diabetes: sulfonylureas, meglitinides, metformin (a biguanide), thiazolidinediones, and α-glucosidase inhibitors. Other classes are also mentioned in literature.In this work, different types of genetic mutations (mutations of the gene for glucokinase, HNF 1α, HNF1β and Kir6.2 and SUR1 subunit of KATP channel, PPAR-γ, OCT1 and OCT2, cytochromes, direct drug-receptor (KCNJ11), as well as the factors that influence the development of the disease (TCF7L2) and variants of genes that lead to hepatosteatosis caused by thiazolidinediones) and their influence on the response to therapy with oral antidiabetics will be reviewed.     

Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease. Several classes of drugs are currently available to treat T2DM patients; however, clinical response to these drugs often exhibits significant variation among individuals. For the oral antidiabetic drug classes of sulfonylureas, nonsulfonylurea insulin secretagogs, biguanides and thiazolidinediones, pharmacogenomic evidence has accumulated demonstrating an association between specific gene polymorphisms and interindividual variability in their therapeutic and adverse reaction effects. These polymorphisms are in genes of molecules involved in metabolism, transport and therapeutic mechanisms of the aforementioned drugs. Overall, it appears that pharmacogenomics has the potential to improve the management of T2DM and help clinicians in the effective prescribing of oral antidiabetic medications. Although pharmacogenomics can explain some of the heterogeneity in dose requirements, response and incidence of adverse effects of drugs between individuals, it is now clearly understood that much of the diversity in drug effects cannot be solely explained by studying the genomic diversity. Epigenomics, the field that focuses on nongenomic modifications that influence gene expression, may expand the scope of pharmacogenomics towards optimization of drug therapy. Therefore, pharmacoepigenomics, the combined analysis of genetic variations and epigenetic modifications, holds promise for the realization of personalized medicine. Although pharmacoepigenomics has so far been evaluated mainly in cancer pharmacotherapy, studies on epigenomic modifications during T2DM development provide useful data on the potential of pharmacoepigenomics to elucidate the mechanisms underlying interindividual response to oral antidiabetic treatment. In summary, the present article focuses on available data from pharmacogenomic studies of oral antidiabetic drugs and also provides an overview of T2DM epigenomic research, which has the potential to boost the development of pharmacoepigenomics in antidiabetic treatment.     

Pharmacogenomics of the OATP and OAT families

Drug disposition is highly dependent on the interplay between drug metabolism and transport in organs such as the intestine, kidney, and liver. Genetically determined variation in drug transporter function or expression is now increasingly recognized to have a significant role as a determinant of intersubject variability in drug response. Similar to the discoveries of functional genetic variations in drug efflux transporters, such as multi-drug resistance proteins 1 and 2, there have been considerable advances in the identification of single nucleotide polymorphisms in transporters that facilitate cellular drug uptake. Among the uptake transporters, members of the organic anion-transporting polypeptides and organic anion transporters can mediate the cellular uptake of a large number of structurally divergent compounds. Accordingly, functionally relevant polymorphisms in these transporters may contribute to interindividual and interethnic variability in drug disposition and response. In this review, recent progress relating to pharmacogenomics of organic anion transporters will be outlined along with a compilation of currently known genetic polymorphisms.     

Pharmacogenetics of irinotecan,doxorubicin and docetaxel transporters in Asian and Caucasian cancer patients: a comparative review

Drug efflux and influx transporters play critical roles in regulating the cellular drug disposition and modulating the pharmacokinetics and pharmacodynamics of anti-cancer agents, which may potentially alter treatment outcomes. The efficiency of drug transport is often dependent on the expression and activity of these membrane-bound proteins, factors which have been shown to be regulated by genes that are known to be highly polymorphic in different ethnic populations. The role of drug transporters becomes even more critical for anti-cancer agents due to the narrow therapeutic windows that separate treatment response and toxicities for these agents. Moreover, high inter-individual variability in the disposition of anti-cancer agents often results in variable treatment outcomes among patients receiving standard doses of the same drug. Such variability has been attributed at least in part to polymorphisms in genes encoding drug-metabolizing enzymes and transporter. To date, numerous pharmacogenetic studies have investigated the associations between variants in the ABC and SLC transporters genes with drug disposition, treatment outcomes and drug-induced toxicities. However, the strengths of these associations and their clinical relevance in different ethnic populations have not been critically examined. This review aims to summarize and evaluate the implications of pharmacogenetic variants in the ABC and SLC transporters genes on the pharmacokinetics and clinical outcomes of three anti-cancer agents: irinotecan, docetaxel and doxorubicin in Caucasian and Asian patients.     

我院2001～2004年口服抗糖尿病药物应用分析

目的了解我院口服抗糖尿病药的用药情况及发展趋势,为临床合理用药提供参考。方法采用金额排序法和频度分析法对我院2001～2004年口服抗糖尿病药物应用情况进行统计分析。结果我院口服抗糖尿病药物用药金额2004年是2001年的3.58倍,用药频率2004年是2001年的2.22倍,以阿卡波糖、格列吡嗪、格列齐特、格列喹酮和盐酸二甲双胍的临床使用为最多。结论口服抗糖尿病药在2型糖尿病的临床治疗中占有重要地位。该类药物近年来发展较快,合理用药十分重要。     

Drug transporters: their role and importance in the selection and development of new drugs

Drug transporters expressed in various tissues play a significant role in drug disposition. By regulating the function of such transporters, it may be possible to eventually develop drugs with ideal pharmacokinetic profiles. In this article, we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug development process. The ability to manipulate transporter function offers the opportunity of being able to deliver a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side-effects), controlling the elimination process, and/or improving oral bioavailability. During drug development, it would be very useful to be able to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The use of specific inhibitors of transporters is also an attractive approach to controlling drug disposition, leading to improved efficacy. Currently, optimizing the pharmacokinetic properties of a drug during the early stages of its development is widely accepted as being of great importance. High-throughput screening systems using transporter gene transfected cells or computational (in silico) approaches are efficient tools for assessing transport activity during the early stage of drug development. In addition, drug-drug interactions involving drug transporters and functional genetic polymorphisms of drug transporters are also described. It would also be extremely valuable to be able to quantitatively predict inter-individual pharmacokinetic differences caused by transporter polymorphisms or pharmacokinetic changes caused by drug-drug interactions involving transporters during drug development.     

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.     

Clinical pharmacogenetics of methotrexate

It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and toxicity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecules) as well as pharmacokinetic and pharmacodynamic parameters. A growing body of in vitro and clinical evidence suggests that common polymorphisms in the folate gene pathway are associated with an altered response to methotrexate (MTX) in patients with malignancy and autoimmune disease. Such polymorphisms may also induce significant MTX toxicity requiring expensive monitoring and treatment. Although the available data are not conclusive, they suggest that in the future MTX pharmacogenetics could play a key role in clinical practice by improving and tailoring treatment. This review describes the genetic polymorphisms that significantly influence MTX resistance, efficacy, and toxicity.     

口服降糖药的遗传药理学研究进展

糖尿病是一种受多基因和环境因素共同影响的代谢性疾病。药物代谢酶、受体和转运体的遗传多态性对口服降糖药的体内代谢和降糖疗效有重要作用。本文从细胞色素P450酶、转运体和受体多态性方面对5种主要口服降糖药（磺脲类、噻唑烷二酮类、氯茴苯酸类、双胍类、α-葡萄糖甙酶抑制剂）的体内代谢和药物效应的影响作一综述。     

Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts

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.     

Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implication for pharmacogenetics and disease

The ATP-binding cassette (ABC) transporter genes are ubiquitous in the genomes of all vertebrates. Some of these transporters play a key role in xenobiotic defense and are endowed with the capacity to efflux harmful toxic substances. A major role in the evolution of the vertebrate ABC genes is played by gene duplication. Multiple gene duplication and deletion events have been identified in ABC genes, resulting in either gene birth or gene death indicating that the process of gene evolution is still ongoing in this group of transporters. Additionally, polymorphisms in these genes are linked to variations in expression, function, drug disposition and drug response. Single nucleotide polymorphisms in the ABC genes may be considered as markers of individual risk for adverse drug reactions or susceptibility to complex diseases as they can uniquely influence the quality and quantity of gene product. As the ABC genes continue to evolve, globalization will yield additional migration and racial admixtures that will have far reaching implications for the pharmacogenetics of this unique family of transporters in the context of human health.     

The Influence of Oral Antidiabetic Drugs on Cellular Drug Uptake Mediated by Hepatic OATP Family Members

As patients with type 2 diabetes receiving oral antidiabetic drugs are often concomitantly treated with other drugs, they are of increased risk for drug interactions. Drugs have to be taken up into hepatocytes before their intracellular drug action or before they are metabolized, and therefore, uptake transporters are important modulators of drug pharmacokinetics and drug effects. To gain more insights into the role of uptake transporters for drug interactions, we investigated whether frequently prescribed oral antidiabetic drugs interact with the transport of drugs, mediated by the hepatic uptake transporters OATP1B1 (gene symbol SLCO1B1), OATP1B3 (gene symbol SLCO1B3) and OATP2B1 (gene symbol SLCO2B1). Using HEK293 cells recombinantly over‐expressing these uptake transporters, we analysed whether glibenclamide, glimepiride, nateglinide and pioglitazone influence the transport of the model transport substrate bromosulfophthalein. Furthermore, we investigated the influence of the same oral antidiabetic drugs and of repaglinide and rosiglitazone on the uptake of the HMG‐CoA‐reductase inhibitor atorvastatin. The oral antidiabetic drugs glibenclamide, glimepiride and nateglinide inhibited the transport of the model substrate bromosulfophthalein, particularly the OATP2B1‐mediated uptake. The OATP‐mediated atorvastatin uptake was inhibited in a similar manner. For glibenclamide, inhibitory constants (K_i values) of 13.6 μM, 8.1 μM and 0.5 μM for OATP1B1‐, OATP1B3‐ and OATP2B1‐mediated BSP uptake were determined. In conclusion, these in vitro results demonstrate that several oral antidiabetic drugs may influence hepatic OATP‐mediated drug uptake. The in vivo consequences of these results have to be analysed in further studies.     

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.     

Intercommunity variations in antidiabetic drug utilization and in prevalence of diabetes mellitus

In order to assess whether differences in the extent of antidiabetic drug utilization may be an indicator of variations in diabetes prevalence (Type 1 plus Type 2, including non-pharmacologically treated diabetics), intercommunity variations of antidiabetic drug utilization (insulin plus oral agents) in Sweden were examined through sales expressed in defined daily doses per 1000 inhabitants per day and compared with intercommunity prevalence variations. There were large (two-fold) and long-lasting (>10 years) between-county differences in antidiabetic drug sales. Low-sales counties were found both in the doctor-dense south and the doctor-sparse north of Sweden, which argues against the assumption that the sales variation simply was due to different access to medical care. Recent diabetes prevalence figures have been obtained for eight municipalities in different parts of Sweden. In these, antidiabetic drug sales and diabetes prevalence (including non-pharmacologically treated diabetics) showed a close correlation (r = 0.87; p < 0.01), supporting the assumption that variations in antidiabetic drug utilization may indicate variations in diabetes prevalence, at least in countries that, like Sweden, have uniform health care systems. The findings also suggest that, in Sweden, there is little intercommunity variation in the proportion of non-pharmacologically treated diabetics. On the other hand, it is likely that there are many undetected diabetics in areas where no diabetes screening has been performed. Hence, although differences in antidiabetic drug sales may help to indicate where to look for differences in diabetes prevalence, drug sales data are no substitutes for prevalence studies.