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。     

转运体在药物胆汁排泄中的作用

目的:综述转运体在药物胆汁排泄中的作用。方法:以近几年国内外研究文献为基础,从转运体介导药物的胆汁排泄过程、介导药物胆汁排泄的转运体、药物相互作用、转运体的基因多态性等方面进行综述。结果:转运体对药物体内经胆汁排泄过程、临床用药安全性、用药后的个体差异等方面均存在影响。结论:随着对转运体认识的不断深入,其将在药物设计、临床合理用药、个体化治疗等方面发挥重要作用。     

肾脏转运体介导抗病毒药物肾排泄的研究进展

目的:了解肾脏转运体介导抗病毒药物肾排泄的研究现状,为临床合理用药提供参考.方法:对近年抗病毒药物与肾脏转运体相关的文献进行综述.结果:有机阴离子转运体(Organic Anion Transporters,OAT1～3)和有机阳离子转运体(Organic Cation Transporters,OCT1～3)介导药物流入细胞内,而ATP结合转运体(ATP Binding Cassette,P-gp,MRP2～5)介导药物从细胞排出.寡肽转运体(Peptide Transporters,PEPT1～2)介导伐昔洛韦双向扩散.结论:通过介导药物的摄取和排出,肾脏转运体在调节体内常用抗病毒药物浓度时发挥重要的作用.     

肾脏转运体及其研究方法

肾脏是机体重要器官之一,主要承担着体内代谢产物、药物以及毒物等物质的排泄。因此明确各物质在肾脏排泄机制有利于提高药物的安全性,避免不良反应,可为指导临床合理用药提供理论依据。本文介绍了肾脏中介导药物分泌与重吸收的转运体,阐述了通过体内、体外方法预测药物经肾脏转运体在肾脏的转运以及排泄机制。此外,还概括了研究肾脏转运体的主要研究方法,为基础以及临床实验提供参考。     

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。     

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。     

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.     

转运体在药物经肝脏清除过程中的作用

肝脏在药物的体内清除过程中具有重要作用,它不仅是药物代谢的主要场所,还控制着药物及其代谢物的胆汁排泄过程。转运体是控制细胞内外物质传输的一类功能性膜蛋白,其在肝脏有广泛表达,并能对药物进入肝细胞以及排泄至胆汁的过程进行调控,因而,对于肝脏清除过程具有重要作用。本文从肝脏中重要转运体的分布、功能以及底物选择性出发,对其在药物的肝脏清除中的作用、由其引起的药物药物相互作用以及重要转运体的基因多态性研究进行了综述。     

转运蛋白在药物肾脏转运中的重要作用

肾脏转运蛋白对药物在体内排泄和重吸收过程重要作用.本文对肾脏转运蛋白的种类、分布、作用机制及其对药物排泄过程的影响和可能产生的药物相互作用做了综述.     

肾脏中转运体对核苷类抗病毒药物的转运作用

药物转运体在药物的药动学和药效学过程中发挥重要作用,而核苷类抗病毒药物与其他药物的相互作用主要基于肾小管膜上表达的转运体。本论文分别对肾脏中参与核苷类抗病毒药物转运的转运体,几种主要核苷类抗病毒药物以及它们之间相互作用的研究现状进行了综述。     

Hepatic drug transporters: the journey so far

Introduction: The key role of transporter biology in both the manifestation and treatment of disease is now firmly established. Experiences of sub-optimal drug exposure due to drug-transporter interplay have supported incorporation of studies aimed at understanding the interactions between compounds and drug transporters much earlier in drug discovery. While drug transporters can impact the most pivotal pharmacokinetic parameter with respect to human dose and exposure projections, clearance, at a renal or hepatobiliary level, the latter will form the focus of this perspective.

Areas covered: A synopsis of guidelines on which transporters to study together with an overview of the currently available toolkit is presented. A perspective on when to conduct studies with various hepatic transporters is also provided together with structural “alerts” which should prompt early investigation.

Expert opinion: Great progress has been made in individual laboratories and via consortia to understand the role of drug transporters in disease, drug disposition, drug-drug interactions and toxicity. A systematic analysis of the value posed by the available approaches and an inter-lab comparison now seems warranted. The emerging ability to use physico-chemical properties to guide future screening cascades promises to revolutionise the efficiency of early drug discovery.     

转运蛋白在药物肝胆转运中的重要作用转运蛋白在药物肝胆转运中的重要作用

近年来随着生物膜转运相关技术的进步,在肝中证明存在许多与药物胞内摄取和胞外分泌相关的转运蛋白,它们在药物肝胆转运中的重要性也渐渐被重视。1994年前后,相继克隆出各种药物转运蛋白的基因,并通过基因转染细胞和基因敲除动物的研究,对载体介导膜转运的认识提高到了分子基因     

寡肽转运体在生理、药物转运的重要作用及临床相关性

寡肽转运体（PEPTs）属于溶质转运体（SLC）大家族,以H⁺梯度为驱动力,包括PEPT1和PEPT2。PEPT1是低亲和力、高容量转运蛋白,主要表达于小肠;而PEPT2是高亲和力、低容量的转运蛋白,主要在肾脏、脑和肺中表达,在生物体中分布较广。PEPTs除重吸收二肽和三肽以及维持脑中神经肽的稳态作用外,还能够吸收和处置许多重要的化合物,如一些氨基头孢菌素、血管紧张素转化酶抑制剂、抗病毒前药等,而且PEPTs也与一些肠道疾病和癌症相关。因此综述了PEPTs在生理、药物转运中的重要作用及临床相关性。     

转运体介导的药物相互作用对药物吸收的影响及其临床意义

目前,临床实践中使用的大多数药物是经口服给药,必须经过充分和持续地吸收才能达到效果。药物吸收在口服药物治疗疾病中起着先决条件,其中药物转运体在药物的肠道吸收中起主要作用。同时药物的联合应用在临床上越来越普遍,通常通过使用多种药物来达到治疗效果,但联合用药大多会产生一定的药物相互作用,从而影响药物的药动学特点。综述肠道转运体介导的几类药物相互作用对其吸收的影响及临床意义,为临床应用提供参考。     

Benzylpenicillin inhibits the renal excretion of acyclovir by OAT1 and OAT3

BackgroundAcyclovir is acyclic guanosine derivative. Benzylpenicillin (PCG) is a β-lactam antibiotic. The purpose of this study was to investigate the pharmacokinetic drug-drug interaction (DDI) between PCG and acyclovir.MethodWhen acyclovir and PCG were co-administered, plasma concentration of acyclovir, urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/hOAT3- HEK293 cells were determined to examine the effect of PCG on urinary excretion of acyclovir.ResultsThe plasma concentration of acyclovir was increased markedly and accumulative renal excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with PCG. PCG could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-human embryonic kidney (HEK293) cells.ConclusionsIt indicates that acyclovir is a substrate for OAT1 and OAT3. PCG inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. These results suggest important information for DDI between PCG and acyclovir in kidney.     

The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3–31.31), plasma clearance (249–288 ml/min), and renal clearance (151–177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54±6, 19±4, 6.5±0.7 and 5.5±0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3±0.4, 2.2 ±0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83±0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 ±226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 ±241). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92–94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0–1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.     

Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption

Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).     

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。