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。     

代谢酶和转运体介导的中药-西药相互作用的药动学机制研究进展

随着中草药的广泛应用,中药-西药相互作用(herb-drug interaction,HDI)问题日益凸显。代谢酶和转运体是影响药物体内处置过程的重要因素,其表达和功能的改变常常引起药代动力学的变化,是药物相互作用的主要靶点。代谢酶负责药物的代谢清除,主要包括细胞色素P450超家族(CYP)、UDP-葡萄糖醛酸基转移酶(UGT)以及磺酸化酶(SULT);转运体参与药物的口服吸收、体内分布以及排泄,主要包括肠道转运体、肾脏转运体、肝脏转运体以及脑转运体等。葛根、银杏叶、人参、圣约翰草等中草药在临床上应用广泛,且常与西药联合应用,其成分与代谢酶以及转运体存在相互作用,容易产生HDI。本文综述代谢酶、转运体介导的HDI的药代动力学机制,阐述常用中草药在与西药联合应用时应注意的问题。     

microRNA介导低氧对药物代谢酶和转运体的调控

低氧条件下机体的循环系统、神经系统、内分泌系统等的功能发生显著改变,这些变化影响药物在体内的吸收、分布、代谢和排泄.药物代谢酶和转运体是影响药物代谢的主要因素,微小RNA(microRNA,miRNA)除调控与药物代谢相关的基因如缺氧诱导因子、炎症因子、核受体等,还可直接作用于药物代谢酶和转运体,影响药物的体内代谢.本...     

肾脏转运体和/或代谢酶介导药物排泄及药物相互作用的研究进展

肾脏是人体最重要的排泄器官。肾单元近端小管细胞具有多种药物转运体和代谢酶,在药物及其代谢物处置中发挥关键作用。近端小管细胞中主要转运体包括有机阴离子转运体、有机阳离子转运体、有机阳离子/肉毒碱转运体、多药及毒素外排转运蛋白、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白;主要代谢酶包括细胞色素P450酶,UDP-葡萄糖醛酸基转移酶、磺酸基转移酶、谷胱甘肽S-转移酶。肾脏转运体和/或代谢酶介导药物相互作用(DDIs)是临床关注的重要问题。肾脏转运体和代谢酶存在密切协作关系,在肾脏也存在多种相互作用现象(包括转运-转运相互作用,代谢-代谢相互作用和转运-代谢相互作用),其显著影响药物肾脏处置、临床疗效和肾毒性。本文系统阐述了这些相互作用对药物及其代谢物的肾脏排泄、药动学、DDIs和肾毒性的影响。今后需要进一步阐明肾脏转运-代谢相互作用机制,将有助于研究体内药物肾脏处置和DDIs,促进临床合理用药。     

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。     

转运体和核受体影响药物代谢的研究进展

转运体是存在于体内几乎所有器官上的有转运功能的蛋白,对药物在体内的吸收、分布、代谢和排泄有非常重要的作用.而核受体是存在于细胞内的配体依赖性转录因子,可以激活配体影响代谢酶和转运体的表达和活性,进而影响药物在机体内代谢.本文综述了转运体和核受体家族中几个重要的成员以及它们对药物代谢影响的研究进展.     

药物转运体与药物体内过程

关于药物在机体内的跨膜转运机制,以往的研究多侧重于药物理化性质.近年,发现体内存在多种转运蛋白(转运体)系统,对药物体内跨膜转运,有重要意义,有时甚至起决定性作用,因此,药物转运体对药物的体内过程,即药物的吸收、分布、代谢和排泄及药物之间的相互作用有重要影响,并可影响或决定药物的动力学过程.     

转运体介导的二甲双胍药物相互作用研究进展

二甲双胍作为治疗2型糖尿病的一线药物广泛应用于临床。多种转运体参与二甲双胍的体内处置过程,对药物的吸收、分布及排泄行为有重要影响。某些药物可影响转运体的功能,当其与二甲双胍联用时,有可能引起后者药动学和药效学的改变,从而导致不良的临床治疗结局。本文通过查阅和分析相关文献,将转运体介导的与二甲双胍相关的药物相互作用作一综述,旨在为二甲双胍的合理应用提供依据。     

药物转运体OAT2研究进展

有机阴离子转运体2(OAT2)属于有机阴离子转运体家族成员,主要分布于肝肾,介导肌酐、尿酸等内源性物质及多种外源性药物的跨膜转运。OAT2对外源性物质如药物的体内过程如吸收、分布、代谢和排泄过程起着重要作用。研究表明OAT2的表达与活性被药物、疾病、性别及基因多态性等多种因素影响,亦受到核受体等信号通路调控。故本文综述药物转运体OAT2的结构与分布、底物、调控机制、临床意义的研究进展,为OAT2可能介导药物相互作用及药物疗效预测提供参考。     

联合用药的药物相互作用及研究方法

随着人们对于疾病的认识越来越深入,联合用药得到越来越普遍的使用,同时所产生的药物间的相互作用也越来越受到关注。联合用药可能通过影响与药物吸收、分布、代谢、排泄等相关的酶、转运体等,以改变药物的药代属性（生物利用度、分布特性等）,调节体内动态药效物质组的构成,改变药物的药效（协同作用、拮抗作用、毒副作用等）,从而对药物的有效性、安全性产生影响。从联合用药对药物吸收与代谢的影响这两方面来阐述联合用药的研究近况,为联合用药的基础研究以及临床应用的安全有效提供参考。     

The Evolving Role of Drug Metabolism in Drug Discovery and Development

Drug metabolism in pharmaceutical research has traditionally focused on the well-defined aspects of absorption, distribution, metabolism and excretion, commonly-referred to ADME properties of a compound, particularly in the areas of metabolite identification, identification of drug metabolizing enzymes (DMEs) and associated metabolic pathways, and reaction mechanisms. This traditional emphasis was in part due to the limited scope of understanding and the unavailability of in vitro and in vivo tools with which to evaluate more complex properties and processes. However, advances over the past decade in separate but related fields such as pharmacogenetics, pharmacogenomics and drug transporters, have dramatically shifted the drug metabolism paradigm. For example, knowledge of the genetics and genomics of DMEs allows us to better understand and predict enzyme regulation and its effects on exogenous (pharmacokinetics) and endogenous pathways as well as biochemical processes (pharmacology). Advances in the transporter area have provided unprecedented insights into the role of transporter proteins in absorption, distribution, metabolism and excretion of drugs and their consequences with respect to clinical drug–drug and drug–endogenous substance interactions, toxicity and interindividual variability in pharmacokinetics. It is therefore essential that individuals involved in modern pharmaceutical research embrace a fully integrated approach and understanding of drug metabolism as is currently practiced. The intent of this review is to reexamine drug metabolism with respect to the traditional as well as current practices, with particular emphasis on the critical aspects of integrating chemistry and biology in the interpretation and application of metabolism data in pharmaceutical research.     

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.     

大蒜对药物代谢酶及转运体活性影响研究进展

作为天然药物的一种,大蒜包含多种具有药理活性的有效成分,在临床应用日益广泛。然而,大蒜长期应用,可能对肝脏药物代谢酶及体内药物转运体的活性产生诱导或抑制效应,从而引起自身或其他合用药物代谢的改变和导致药物相互作用的发生。     

肝脏“代谢-转运互作”及其对药物药代动力学、疗效和毒性影响的研究进展

肝脏是药物代谢和排泄的主要器官。肝脏药物代谢酶和膜转运体对肝细胞内药物处置及其临床疗效和毒性产生重要影响。近年来,国内外学者发现被称为"代谢-转运互作"的动力学现象,其对药物药代动力学(生物利用度)、药物相互作用具有显著影响。药物代谢酶与转运体间的功能相互作用是目前药物代谢和药代动力学研究的热点之一。本文对肝脏代谢-转运互作进行了探究,并系统阐述了这种互作对药物(特别是Ⅱ相药物代谢)的药物相互作用、药代动力学、临床疗效和毒性反应的影响。今后应进一步阐明肝脏代谢-转运互作机制,有助于研究体内药物处置及药物相互作用,为临床合理用药提供新思路和新技术。     

体内药物相互作用机制及其评价方法的研究进展

药物–药物相互作用是目前临床不良反应的主要来源之一,药物相互作用产生的效益和风险会严重影响药物的安全性和有效性。根据药物在体内的过程,分别从吸收、分布、代谢、排泄4个方面阐述了体内药物相互作用机制并佐以实例;潜在药物相互作用的研究以预测其可能发生的药物相互作用也已成为药物开发的必须过程,综述了近些年比较成熟的药物相互作用评价模型的及其研究进展。     

肠道药物转运体及其研究方法

口服药物在肠道中的吸收是决定药物生物利用度的重要因素。肠道中有许多药物膜转运蛋白介导药物的吸收、分布、排泄及药物相互作用等。明确其转运机制有利于提高药物的安全性和有效性,从而指导临床合理用药。通过体内外方法预测药物经转运体在肠道中的转运情况。本文介绍了肠道内转运药物的主要膜转运蛋白,阐述了口服药物经肠道转运机制,概括了研究肠道药物转运体的主要研究方法,并对多种体内外转运体研究方法的优缺点进行了比较。     

Development of an ADME and drug–drug interactions knowledge database for the acceleration of drug discovery and development

It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE^® ADME/DDI (drug–drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug–drug interactions.