Functional interaction of intestinal CYP3A4 and P‐glycoprotein

Abstract

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.