肝脏和肾脏中转运体介导清除率的体外-体内外推法。

In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney.

作者信息

Kusuhara Hiroyuki, Sugiyama Yuichi

机构信息

The University of Tokyo, Japan.

出版信息

Drug Metab Pharmacokinet. 2009;24(1):37-52. doi: 10.2133/dmpk.24.37.

Abstract

Transporters govern drug movement into and out of tissues, thereby playing an important role in drug disposition in plasma and to the site of action. The molecular cloning of such transporters has clarified the importance of members of the solute carrier family, such as OATP/SLCO, OCT/SLC22, OAT/SLC22, and MATE/SLC47, and the ATP-binding cassette transporters, such as P-glycoprotein/ABCB1, MRPs/ABCC, and BCRP/ABCG2. Elucidation of molecular characteristics of transporters has allowed the identification of transporters as mechanisms for drug-drug interactions, and of interindividual differences in drug dispositions and responses. Cumulative studies have highlighted the cooperative roles of uptake transporters and metabolic enzymes/efflux transporters. In this way, the concept of a rate-limiting process in hepatic/renal elimination across epithelial cells has developed. This review illustrates the concept of the rate-limiting step in the hepatic elimination mediated by transporters, and describes the prediction of the in vivo pharmacokinetics of drugs whose disposition is determined by transporters, based on in vitro experiments using pravastatin as an example. This review also illustrates the transporters regulating the peripheral drug concentrations.

摘要

转运体控制药物进出组织,因此在药物在血浆中的处置以及到达作用部位的过程中发挥着重要作用。此类转运体的分子克隆已阐明溶质载体家族成员的重要性,如有机阴离子转运多肽/OATP/SLCO、有机阳离子转运体/OCT/SLC22、有机阴离子转运体/OAT/SLC22和多药及毒素排出蛋白/MATE/SLC47,以及ATP结合盒转运体,如P-糖蛋白/ABCB1、多药耐药相关蛋白/MRPs/ABCC和乳腺癌耐药蛋白/BCRP/ABCG2。对转运体分子特征的阐明使得人们能够将转运体确定为药物相互作用的机制,以及药物处置和反应的个体间差异的机制。累积研究突出了摄取转运体与代谢酶/外排转运体的协同作用。通过这种方式,跨上皮细胞的肝脏/肾脏消除中的限速过程的概念得以发展。本综述阐述了由转运体介导的肝脏消除中的限速步骤的概念,并以普伐他汀为例,基于体外实验描述了其处置由转运体决定的药物的体内药代动力学预测。本综述还阐述了调节外周药物浓度的转运体。

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