Wang Shuai, Xing Huijie, Zhao Mengjing, Lu Danyi, Li Zhijie, Dong Dong, Wu Baojian
International Ocular Surface Research Center and Institute of Ophthalmology, Jinan University Medical School, Guangzhou, China.
Department of Pharmaceutics, College of Pharmacy, Jinan University, 601 Huangpu Road West, Guangzhou, Guangdong 510632, China.
Curr Drug Metab. 2016;17(10):922-929. doi: 10.2174/1389200217666161128150835.
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.
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.
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 (CLapp) and total metabolism (fmet), as well as an increase in the intracellular level of metabolite (Ci). 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.
Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay.
在制药领域，对代谢 - 转运相互作用的机制性理解具有重要意义，因为该知识有助于解释药物/外源性物质的代谢和处置研究以及体内药物 - 药物相互作用。大约10年前，人们开始认识到细胞II相代谢受到生成代谢物的排泄（外排转运）的强烈影响，这种动力学现象被称为“II相代谢 - 转运相互作用”。据信这种相互作用对经历II相代谢的药物/化学物质的药代动力学（生物利用度）有显著影响。
在本文中，我们综述了使用细胞模型、灌注大鼠肠道和完整大鼠研究II相代谢 - 转运相互作用的研究。还总结了探索这种相互作用时潜在的混杂因素。此外，还讨论了II相代谢 - 转运相互作用的潜在机制。
各种针对工程细胞和啮齿动物的研究表明，II相酶和外排转运体之间存在相互作用。这种相互作用主要是指II相（结合）代谢对外排转运体活性的依赖性。一般来说，抑制外排转运体或降低其表达会导致代谢物排泄、表观排泄清除率（CLapp）和总代谢（fmet）降低，以及代谢物细胞内水平（Ci）升高。基于药代动力学建模/模拟、细胞和动物研究，水解酶介导的去结合（作为“桥梁”）对于相互作用的发生至关重要。水解酶连接了两个过程（即代谢物形成和排泄）并使其相互作用成为可能（桥梁效应）。没有这座“桥梁”，代谢物形成独立于其下游的排泄过程，因此代谢物排泄对其形成的影响就不可能发生。
去结合（由水解酶介导）在结合 - 转运相互作用中起重要作用。
