Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition

Author(s): Shaojun Shi, Yunqiao Li.

Journal Name: Current Drug Metabolism

Volume 15 , Issue 10 , 2014

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Abstract:

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.

Keywords: drug interactions, drug-metabolizing enzymes, drug transporters, genetic variations, interplay, mechanisms, pharmacokinetics.

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Article Details

VOLUME: 15
ISSUE: 10
Year: 2014
Page: [915 - 941]
Pages: 27
DOI: 10.2174/1389200216666150401110610
Price: $65

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