Strategies to overcome simultaneous P-glycoprotein mediated efflux and CYP3A4 mediated metabolism of drugs.
Cytochrome P450 3A4 (CYP3A4), abundant in both the liver and upper intestinal enterocytes, limits the systemic bioavailability of xenobiotics. P-glycoprotein (P-gp), the MDR1 gene product, is also known to reduce the oral bioavailability of the drug molecules. High cellular expression of P-gp and CYP3A4 in mature intestinal enterocytes and their similar substrate specificity suggest that the function of these proteins may be complementary and may form a co-ordinated intestinal barrier. Various ongoing preclinical and clinical studies have demonstrated that the oral bioavailability of various P-gp and/or CYP3A4 substrates can be increased by simultaneous administration of P-gp and/or CYP3A4 inactivators. The current review describes the background and summarises several proposed hypotheses in modifying oral bioavailability by various drug-inhibitor interactions.
Patel
J
J
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.
Mitra
A K
AK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D018565:Food-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D015262:Xenobiotics / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human