Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition.
Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition.
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DOI：
10.2174/1389200216666150401110610
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发表时间：
2014-11
影响因子：
2.3
通讯作者：
S. Shi;Yunqiao Li
中科院分区：
文献类型：
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作者：
S. Shi;Yunqiao Li
近年来，药物代谢酶（DMEs）和药物转运蛋白（DTs）在药物吸收和处置过程中的相互作用以及复杂的药物相互作用（DI）已成为一个有趣的话题，也被称为“转运-代谢相互作用”。首先讨论了目前对这种相互作用的机械理解。在本文中，研究细胞色素P450酶（CYP）和外排转运蛋白之间的相互作用进行了系统的审查，在体外，原位，在硅片，在动物和人类，其次是CYP摄取转运蛋白，CYP摄取转运蛋白外排转运蛋白，和II期代谢酶转运蛋白相互作用的研究。尽管一些细胞、离体器官和整体动物研究，结合模拟和建模，已经解决了DME和DT可以协同作用影响共享底物药物生物利用度的问题，但在人体研究中仍然缺乏令人信服的证据。此外，DME和DT之间的功能相互作用将是高度底物和剂量依赖性的。此外，我们回顾了最近的研究，以评估遗传变异的影响之间的相互作用的DME和DT，这可能有助于更准确地预测药代动力学（PK）和可能的DI在人体内。有强有力的证据表明，协调调节DEM和DT基因表达和蛋白质活性（如核受体）。总之，迫切需要进一步的调查和分析，以探讨DME和DT的功能相互作用，并描绘潜在的机制。
In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the "transport-metabolism interplay". The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs-uptake transporters, CYPs-uptake transporters-efflux transporters, and phase II metabolic enzymes-transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms.