title: 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.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. kari.kivisto@ikp-stuttgart.de
authors.forename: Kari T
authors.initials: KT
authors.lastname: Kivistö
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D020895:Enterocytes / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D023421:Models, Animal; D010599:Pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human