Pluronic block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier

Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents. Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular, the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic in enhancing the blood-brain barrier (BBB) penetration of drugs.     

大黄酸对药物转运体和代谢酶影响的研究进展

药物转运体和药物代谢酶是影响药物体内处置过程中至关重要的因素。大黄酸作为传统中药大黄的主要活性成分,具有广泛药理活性。研究发现,大黄酸与药物转运体和代谢酶密切相关,能够直接激活或抑制多种转运体的功能及其蛋白表达。而且大黄酸对药物代谢酶细胞色素P450（CYP450）的功能及其蛋白表达同样有抑制作用。因此,大黄酸与其他药物合用时,可能发生基于药动学的药物相互作用（drug-drug interaction,DDI）。从药物转运体和代谢酶的体内分布、大黄酸对转运体及代谢酶的影响等方面进行综述。     

Current progress in identifying endogenous biomarker candidates for drug transporter phenotyping and their potential application to drug development

Drug transporters play important roles in the elimination of various compounds from the blood. Genetic variation and drug–drug interactions underlie the pharmacokinetic differences for the substrates of drug transporters. Some endogenous substrates of drug transporters have emerged as biomarkers to assess differences in drug transporter activity—not only in animals, but also in humans. Metabolomic analysis is a promising approach for identifying such endogenous substrates through their metabolites. The appropriateness of metabolites is supported by studies in vitro and in vivo, both in animals and through pharmacogenomic or drug–drug interaction studies in humans. This review summarizes current progress in identifying such endogenous biomarkers and applying them to drug transporter phenotyping.     

Herb-drug interactions involving drug metabolizing enzymes and transporters

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity. The herb-drug combinations may reduce a drug efficacy and lead to treatment failure when long-term administration. Case reports detailing serious clinical adverse reactions have promoted studies on the interactions between herbs and drugs. This review highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Drug transporters are widely present in body and play an important role in the absorption, distribution, excretion and metabolism, efficacy, and toxicity of drugs. Investigation of transporters has developed rapidly since 1990s, the effects of many transporters on the pharmacokinetics of drugs and herb-drug interactions have been reported. Some concepts on drug transporters issued experimentally and clinically drug-drug and herb-drug interactions have applied in many studies. Methodology studies are very important for understanding the mechanism, considerations and evaluation of experiments and clinical studies on drug metabolizing enzymes and transporters in drug-drug interactions.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

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 their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

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 their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

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.     

Transporter-mediated Drug Interactions

Since 1994, researchers have isolated various genes encoding transporter proteins involved in drug uptake into and efflux from tissues that play key roles in the absorption, distribution and secretion of drugs in animals and humans. The pharmacokinetic characteristics of drugs that are substrates for these transporters are expected to be influenced by coadministered drugs that work as inhibitors or enhancers of the transporter function. This review deals with recent progress in molecular and functional research on drug transporters, and then with transporter-mediated drug interactions in absorption and secretion from the intestine, secretion from the kidney and liver, and transport across the blood-brain barrier in humans. Although the participation of the particular transporters in observed drug-drug interactions can be difficult to confirm in humans, this review focuses mainly on pharmacokinetic interactions of clinically important drugs.     

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Drug–drug interactions (DDIs) caused by the co-administration of multiple drugs are major safety concerns in the clinic. Several drugs have been withdrawn from the market due to perpetrator or victim DDIs. Strategies have been developed to assess DDI risks early in drug discovery to reduce DDI liabilities. High-to-medium throughput assays are available to identify undesirable scaffolds and to guide structural modifications to minimize DDIs. Definitive methods are used at later stages of drug discovery and development to provide a more accurate measurement of DDI parameters and to enable clinical translations. Physiologically based pharmacokinetic modeling and simulations are powerful tools to accurately predict DDIs and to assess risks in the clinic. Although significant advances have been made over the years, many challenges remain for clinical DDI translations. This includes DDIs involving non-cytochrome P450 enzymes, transporters, enzyme-transporter interplay, indirect effects from biologics, and pharmacodynamic based DDI. This review focuses on methods that are used to assess hepatic DDIs caused by enzyme inhibition and induction.     

药物转运体介导的中药及单体药物相互作用的研究进展

药物转运体在中药及单体成分的体内吸收、分布和排泄过程中发挥着重要的作用。中药及单体对药物转运体的功能和表达可产生诱导或抑制作用,从而影响这些转运体底物的体内处置过程。随着中药药动学的发展,基于转运体介导的中药及单体体内处置研究越来越受到重视。该文对药物转运体介导的中药及单体药动学的研究进行综述。     

Effects of Drug Transporters on Volume of Distribution

Recently, drug transporters have emerged as significant modifiers of a patient’s pharmacokinetics. In cases where the functioning of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity, as well as a change in half life independent of a change in clearance. Here, we review pharmacokinetic interactions at the transporter level that have been investigated in animals and humans and reported in literature, with a focus on the changes in distribution volume. We pay particular attention to the differing effects of changes in transporter function on the three measures of volume. Further, trends are discussed as they may be used to predict volume changes given the function of a transporter and the primary location of the interaction. Because the liver and kidneys express the greatest level and variety of transporters, we denote these organs as the primary location of transporter-based interactions. We conclude that the liver is a larger contributor to distribution volume than the kidneys, in consideration of both uptake and efflux transporters. Further, while altered distribution due to secondary interactions at tissues other than the liver and kidneys may have a pharmacodynamic effect, these interactions, at least at the blood-brain barrier, do not appear to significantly influence overall distribution volume. The analysis provides a framework for understanding potential pharmacokinetic interactions rooted in drug transporters as they modify drug distribution.     

The Øie-Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

INTRODUCTION: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical ?ie-Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. AREAS COVERED: In this review, the suitability of the ?ie-Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the ?ie-Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the ?ie-Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. EXPERT OPINION: The ?ie-Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.     

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。     

转运体在药物排泄中的作用及在新药研发中的意义

本文介绍了药物转运体在药物排泄过程中的作用,探讨了其在新药研发和临床应用中的可能性。通过对药物转运体功能的了解和利用,可以开发出对某些器官有靶向性的药物,或避免药物分布到某些器官中,从而提高药物的疗效,降低其毒副作用;也可以通过对转运体介导的药物相互作用及肝肠循环的研究,指导临床更加安全有效的用药。在药物研发的初始阶段,就开始重视其药动学特性,这一观念近年来已被很多人所接受。对药物转运体的深入认识和利用,建立高通量的药物转运体筛选体系,对于加速新药研发的进程将具有极其重要的意义。     

Chirality and pharmacokinetics: an area of neglected dimensionality?

Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as racemates. This situation has changed in recent years as a result of advances in the chemical technologies associated with the synthesis, analysis and preparative scale resolution of the enantiomers of chiral molecules. As a result of the application of these technologies the potential significance of the differential pharmacodynamic and pharmacokinetic properties of the enantiomers present in a racemate have become appreciated. Many of the processes involved in drug disposition, i.e. absorption, distribution, metabolism and excretion, involve a direct interaction with chiral biological macromolecules, e.g. transporters, membrane lipids and enzymes, and following administration of a racemate the individual enantiomers frequently exhibit different pharmacokinetic profiles and rarely exist in a 1:1 ratio in biological fluids. The magnitude of the differences between a pair of enantiomers observed in their pharmacokinetic parameters tends to be relatively modest in comparison to their pharmacodynamic properties. However, the observed stereoselectivity may be either amplified or attenuated depending on the organisational level, e.g. whole body, organ or macromolecular, the particular parameter represents. Differences in parameters involving a direct interaction between a drug enantiomer and a biological macromolecule, e.g. intrinsic metabolite formation clearance and fraction unbound, tend to be largest, and comparison of parameters reflecting the whole body level of organisation, e.g. half-life, clearance, volume of distribution, may well mask significant stereoselectivity at the macromolecular level. In spite of the recent interest in drug chirality relatively limited pharmacokinetic data are available for the enantiomers of a number of commonly used racemic drugs. Factors influencing the stereo-selectivity of drug disposition include: formulation and route of administration; in vivo stereochemical stability, both chemical and enzymatic; drug interactions, both enantiomeric and with a second drug; disease state; age; gender; race; and pharmacogenetics. As a result of such factors estimation of pharmacokinetic parameters, development of complex pharmacokinetic models and plasma-concentration-effect relationships based on 'total' drug concentrations following administration of a racemate are of limited value and potentially useless.     

Modulation of the activity of ABC transporters (P-glycoprotein,MRP2, BCRP) by flavonoids and drug response

The present article aims to review the up-to-date information on the most recent studies of the interaction of flavonoids with ABC transporters, in particular the drug pharmacokinetic consequences of such a relationship. In addition, the modulation of the expression of the ABC transporters by flavonoids is also illustrated. Flavonoids are a large group of plant polyphenols present extensively in our daily diets and herbal products. High intake of isoflavones has been associated with a variety of beneficial effects on several common diseases. These polyphenols interact with ABC drug transporters involved in drug resistance and drug absorption, distribution and excretion. A number of studies have demonstrated inhibition of drug transporters by flavonoids. This flavonoid-ABC-transporter interaction could be beneficial for poorly absorbed drugs but could also result in severe drug intoxication, especially drugs with a narrow therapeutic window. On the other hand, flavonoids are themselves substrates of ABC transporters. These proteins can affect the oral availability and tissue distribution of these compounds, modifying their beneficial effects. The challenge is to find a suitable way to predict harmful drug–flavonoid interactions mediated by these transporters. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:598–617, 2010     

Population Pharmacokinetics of Cyclosporine in Transplant Recipients

A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design was limited to intense blood sampling in small groups of patients during a certain posttransplant period, (2) patient factors were evaluated one at a time to identify their association with the pharmacokinetic parameters, and (3) mean pharmacokinetic parameters often cannot be precisely estimated due to large intraindividual variability. Population pharmacokinetics provides a potential means of addressing these limitations and is a powerful tool to evaluate the magnitude and consistency of drug exposure. Population pharmacokinetic studies of cyclosporine focused solely on developing limited sampling strategies and Bayesian estimators to estimate drug exposure, have been summarized before, and are, therefore, not a subject of this review. The major focus of this review is to describe factors (demographic factors, hepatic and gastrointestinal functions, drug–drug interactions, genetic polymorphisms of drug metabolizing enzymes and transporters) that have been identified to contribute to the large portion of observed variability in the pharmacokinetics of cyclosporine in transplant patients. This review summarizes and interprets the conclusions as well as the nonlinear mixed-effects modeling methodologies used in such studies. A highly diversified collection of structural models, variability models, and covariate submodels have been evaluated and validated using internal or external validation methods. This review also highlights areas where additional research is warranted to improve the models since a portion of model variability still remains unexplained.     

肠道药物转运体对药物吸收的研究进展

药物与体内各种转运体的相互作用是药物体内药动学性质的决定性因素之一。本文从肠道转运体出发,介绍了它们在药物吸收过程中的作用,旨在利用肠道转运体的作用增加药物向组织器官的靶向分布;利用转运体的作用改变药物的消除途径,从而减轻其毒副作用;利用转运体的作用进行新药设计从而避免药物间有害相互作用的产生;最后通过构建转运体的高通量筛选系统模型,进行新化合物筛选和候选药物的药动学机制研究,为新药的开发和临床合理化给药提供新的策略和思路。     

Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications

Abstract

1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug–drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described.

2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created.

3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug–drug interactions as well as in human metabolite testing and risk assessment.

4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.     

A regulatory viewpoint on transporter-based drug interactions

1. Pharmacokinetic drug interactions can lead to serious adverse events and the evaluation of a new molecular entity's (NME) drug-drug interaction potential is an integral part of drug development and regulatory review before its market approval. Clinically relevant interactions mediated by transporters are of increasing interest in clinical development and research in this emerging area and it has been revealed that drug transporters can play an important role in modulating drug absorption, distribution, metabolism and elimination. 2. Acting alone or in concert with drug-metabolizing enzymes transporters can affect the pharmacokinetics and/or pharmacodynamics of a drug. The newly released drug interaction guidance by the US Food and Drug Administration (USFDA) includes new information addressing drug transporter interactions with a primary focus on P-glycoprotein (P-gp, ABCB1). 3. This paper provides a regulatory viewpoint on transporters and their potential role in drug-drug interactions. It first outlines information that might be needed during drug development and ultimately included in new drug application (NDA) submissions to address potential transporter-mediated drug interactions. Next, it explains criteria that may warrant conduct of in vivo P-gp-mediated drug interaction studies based on in vitro assessment. In addition, it includes a review case that describes the evaluation of data suggesting a P-gp-based induction interaction.