Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport

Title:Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport

Volume: 17 Issue: 10

Author(s): Shuai Wang, Huijie Xing, Mengjing Zhao, Danyi Lu, Zhijie Li, Dong Dong and Baojian Wu

Affiliation:

Keywords: Arylsulfatase, bioavailability, interplay, phase II metabolism, SULT, UGT.

Abstract: Background: Mechanistic understanding of the metabolism-transport interplay assumes great importance in pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed “phase II metabolism-transport interplay”. This interplay is believed to have significant effects on the pharmacokinetics (bioavailability) of drugs/chemicals undergoing phase II metabolism.

Methods: In this article, we review the studies investigating the phase II metabolism-transport interplay using cell models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed.

Results: Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay) between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II (conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing their expression causes the reductions in metabolite excretion, apparent excretion clearance (CL_app) and total metabolism (f_met), as well as an increase in the intracellular level of metabolite (C_i). The deconjugation mediated by hydrolase (acting as a “bridge”) is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process excretion, thus impact of metabolite excretion on its formation is impossible.

Conclusion: Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay.

Cite this article as:

Wang Shuai, Xing Huijie, Zhao Mengjing, Lu Danyi, Li Zhijie, Dong Dong and Wu Baojian, Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport, Current Drug Metabolism 2016; 17 (10) . https://dx.doi.org/10.2174/1389200217666161128150835

DOI https://dx.doi.org/10.2174/1389200217666161128150835	Print ISSN 1389-2002
Publisher Name Bentham Science Publisher	Online ISSN 1875-5453