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.     

Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination

Members of the organic anion transporting polypeptide (OATP) family are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. This review focuses on OATP1B1 and -1B3, which are specifically expressed in the liver and considered to be of particular importance for hepatic drug elimination and drug pharmacokinetics. Recent literature has indicated that inhibition of these transporters may result in drug-drug interactions. Furthermore, genetic polymorphisms in the genes encoding OATP1B1 and -1B3 have been described that increase or decrease transport in vitro and in vivo. Alteration of transporter function by either of these mechanisms may contribute to interindividual variability in drug disposition and response. In this review an update of this rapidly emerging field is provided.     

Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs

As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays. We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.     

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。     

Transporter-mediated uptake into cellular compartments

Active transport across biological membranes represents a critical step in the disposition of many drugs. It is now well-established that different efflux and uptake transporters such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) or organic anion transporting polypeptides (OATPs) are involved in the overall disposition and efficacy of numerous compounds. These proteins are mainly expressed at physiological sites of drug absorption and elimination, thus leading to diminished absorption and/or increased transporter-facilitated excretion. Moreover, drug transporters are known to be of protective significance in blood-organ barriers. On the contrary, only little is known about the relevance of transporter function on drug levels within tissues and cellular compartments, i.e. the site of action for many substances. Moreover, the pharmacokinetic processing inside the cell is characterized by uptake, metabolism and elimination. It is gradually being recognized that active uptake and/or efflux transporters may modify target concentrations at the subcellular receptor sites which in turn may have an influence on drug effects. This review will summarize current knowledge about the impact of transporter proteins on drug availability within pharmacologically relevant cellular compartments and tissues as hepatocytes, enterocytes, different blood cell types, brain, and the heart with emphasis on the potential clinical significance of these transporters.     

Transporter-mediated uptake into cellular compartments

Active transport across biological membranes represents a critical step in the disposition of many drugs. It is now well-established that different efflux and uptake transporters such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) or organic anion transporting polypeptides (OATPs) are involved in the overall disposition and efficacy of numerous compounds. These proteins are mainly expressed at physiological sites of drug absorption and elimination, thus leading to diminished absorption and/or increased transporter-facilitated excretion. Moreover, drug transporters are known to be of protective significance in blood–organ barriers. On the contrary, only little is known about the relevance of transporter function on drug levels within tissues and cellular compartments, i.e. the site of action for many substances. Moreover, the pharmacokinetic processing inside the cell is characterized by uptake, metabolism and elimination. It is gradually being recognized that active uptake and/or efflux transporters may modify target concentrations at the subcellular receptor sites which in turn may have an influence on drug effects. This review will summarize current knowledge about the impact of transporter proteins on drug availability within pharmacologically relevant cellular compartments and tissues as hepatocytes, enterocytes, different blood cell types, brain, and the heart with emphasis on the potential clinical significance of these transporters.     

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.     

OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine.

Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.     

The functional consequences of genetic variations in transporter genes encoding human organic anion-transporting polypeptide family members

It is increasingly recognised that uptake transporters of the organic anion-transporting polypeptide (OATP) family play important roles in drug absorption, distribution and excretion. They are expressed in a variety of different tissues, including gut, brain, kidney and liver. Substrates of OATPs include several endogenous substances, such as bile salts and hormones, and drugs such as HMG-CoA reductase inhibitors (e.g., pravastatin), cytotoxic drugs and antibiotics. Recent advances in the pharmacogenetics of OATPs have demonstrated that variations (polymorphisms) in genes encoding human OATPs can explain parts of the interindividual variability in the pharmacokinetics of drugs and, thus, contribute to the interethnic and interindividual variability in drug response. This review focuses on consequences of these genetic variations and summarises in vivo as well as in vitro analyses demonstrating the impact of polymorphisms in genes encoding OATPs on transport and pharmacokinetics of drugs.     

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.     

The role of organic ion transporters in drug disposition: an update

Transporters for organic anions and organic cations in kidney, liver, intestine, brain, and placenta play essential roles in drug disposition. The cloning and characterization of these transporters have significantly advanced our understanding of the molecular and cellular mechanisms of the drug disposition process. This review aims at updating the recent knowledge of general properties, structure-function relationships, and regulation mechanisms of the organic anion transporters (OATs) and the organic cation transporters (OCTs). Such information will be essential for the design and development of new drugs to maximize therapeutic efficacy and minimize drug-induced toxicity as well as unwanted drug-drug interactions.     

Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Interindividual variability in oral drug efficacy and toxicity is commonly observed in all therapeutic areas. Importantly, interindividual variability in drug uptake and metabolism can result in poor drug response, adverse drug reactions, or unfavorable drug-drug interaction. One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes. Pharmacogenetics are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution. Knowledge of the genotype-phenotype correlation and frequency distribution of functional single nucleotide polymorphisms may be a valuable tool for individualizing drug therapy. This information can also be useful for explaining inter-individual and inter-ethnic variations in drug response and/or adverse effects. In this review, we focus on the interplay between efflux transporter (ATP-binding cassette, sub-family B (MDR/TAP), member 1/ABCB1) and cytochrome P450s according to genetic polymorphism.     

Modulatory effects of hormones,drugs, and toxic events on renal organic anion transport

The human body is exposed continuously to a wide variety of exogenous compounds, many of which are anionic compounds. In addition, products of phase II biotransformation reactions are negatively charged, viz. glucuronides, sulfate esters, or glutathiones. Renal transport of organic anions is an important defense mechanism of the organism against foreign substances. The combination of the rate of uptake and efflux and the intracellular disposition of organic anions in the proximal tubule determines the intracellular concentration and the nephrotoxic potential of a compound. Modulation of organic anion secretion is observed after exposure of proximal tubules to various hormones, and the subsequent receptor-mediated response is signaled by protein kinases. Transport of anionic compounds across the basolateral as well as the luminal membrane is modified by activation or inhibition of protein kinases. Protein kinase C activation reduces the uptake of organic anions mediated by the organic anion transporter 1 (OAT1/Oat1) and Oat3 and reduces Mrp2-mediated efflux. In addition, activation of protein kinase C has been shown to inhibit transport by the organic anion transporting polypeptide 1 (Oatp1) across the luminal membrane. Additional protein kinases have been implicated in the regulation of organic anion transport, and the role of nuclear factors in xenobiotic excretion is an emerging field. The physiological regulation of organic anion transporters may also be influenced by exogenous factors, such as exposure to xenobiotics and cellular stress. This commentary discusses the current knowledge of endogenous and exogenous influences on renal anionic xenobiotic excretion.     

Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution

Active transport across biological membranes has become a noticeable factor in the absorption, distribution, and excretion of an increasing number of drugs. Different transmembrane transport systems including organic anion transporters (OATP, solute carrier family SLC21A), organic cation transporters (OCT, SLC22A), dipeptide transporters (PEPT, SLC15A), nucleoside transporters (CNT, SLC28A), monocarboxylate carriers (MCT, SLC2A), and members of the large ATP-binding cassette family (ABC, SLC3A) are involved in drug disposition. Genetic polymorphisms in transport proteins frequently occur and contribute to interindividual differences in the efficacy and safety of pharmatherapy. Currently, the most advanced research has been done on P-glycoprotein (ABCB1, SLC3A1.201.1). Knowledge of this transporter indicates that haplotype analysis rather than association with single nucleotide polymorphisms (SNPs) provides the most appropriate interpretation of pharmacogenetic data from drug transporters. This review gives an overview and update on the pharmacological impact of genetic variants in transmembrane transporters.An erratum to this article can be found at     

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.     

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.     

Role of pharmacogenetics in variable response to drugs: focus on opioids

Pharmacogenetics is the study of the role of genetics in inter-individual variability to drug response and therapy. This review provides a comprehensive report of the present status of pharmacogenetic studies for opioid drugs. Opioid analgesics are widely used clinically for pain management, and inter-patient variability with opioid therapy is often reported. Information on genetic polymorphisms in enzymes, receptors and transporters related to opioid disposition (pharmacokinetics) and pharmacology (pharmacodynamics) is discussed. Pharmacogenetics of enzymes, including the cytochrome P450s and uridine diphosphoglucuronosyltransferases, opioid receptors and the ABC family of transporters, is reviewed. The role of genetic variability in clinical opioid therapy is examined, and relevant clinical trials cited. The present status of opioid pharmacogenetics, promises and challenges and future directions are discussed.     

Pharmacogenomics of MRP Transporters (ABCC1-5) and BCRP (ABCG2)

Elucidation of the key mechanisms that confer interindividual differences in drug response remains an important focus of drug disposition and clinical pharmacology research. We now know both environmental and host genetic factors contribute to the apparent variability in drug efficacy or in some cases, toxicity. In addition to the widely studied and recognized genes involved in the metabolism of drugs in clinical use today, we now recognize that membrane-bound proteins, broadly referred to as transporters, may be equally as important to the disposition of a substrate drug, and that genetic variation in drug transporter genes may be a major contributor of the apparent intersubject variation in drug response, both in terms of attained plasma and tissue drug level at target sites of action. Of particular relevance to drug disposition are members of the ATP Binding Cassette (ABC) superfamily of efflux transporters. In this review a comprehensive assessment and annotation of recent findings in relation to genetic variation in the Multidrug Resistance Proteins 1–5 (ABCC1-5) and Breast Cancer Resistance Protein (ABCG2) are described, with particular emphasis on the impact of such transporter genetic variation to drug disposition or efficacy.