Kivistö Kari T, Niemi Mikko, Fromm Martin F
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Fundam Clin Pharmacol. 2004 Dec;18(6):621-6. doi: 10.1111/j.1472-8206.2004.00291.x.
Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug by P-glycoprotein are major determinants of bioavailability of orally administered drugs. The hypothesis that CYP3A4 and P-glycoprotein may act in concert to limit oral drug bioavailability is attractive from a theoretical point of view. Evidence in support of such an interplay between CYP3A4 and P-glycoprotein comes mainly from a limited number of in vitro and animal studies. Obviously, it is a challenging task to demonstrate in vivo in humans that the function of CYP3A4 and P-glycoprotein in enterocytes is complementary, and results to directly support this concept remain elusive. However, CYP3A4 and P-glycoprotein are clearly an integral part of an intestinal defence system to protect the body against harmful xenobiotics, and drugs that are substrates of both proteins often have a low bioavailability after oral administration. The functional interaction of intestinal CYP3A4 and P-glycoprotein warrants additional study. Further understanding this interplay would be potentially useful during drug development to solve bioavailability problems of new drug entities.
肠道中细胞色素P450 3A4（CYP3A4）介导的生物转化以及P-糖蛋白对吸收药物的主动外排是口服给药药物生物利用度的主要决定因素。从理论角度来看，CYP3A4和P-糖蛋白可能协同作用以限制口服药物生物利用度这一假说很有吸引力。支持CYP3A4和P-糖蛋白之间这种相互作用的证据主要来自有限的体外和动物研究。显然，要在人体中进行体内实验以证明肠细胞中CYP3A4和P-糖蛋白的功能是互补的是一项具有挑战性的任务，而直接支持这一概念的结果仍然难以捉摸。然而，CYP3A4和P-糖蛋白显然是肠道防御系统的一个组成部分，用于保护身体免受有害外源性物质的侵害，并且这两种蛋白的底物药物口服后往往生物利用度较低。肠道CYP3A4和P-糖蛋白的功能相互作用值得进一步研究。进一步了解这种相互作用在药物研发过程中对于解决新药物实体的生物利用度问题可能会有帮助。
