title: Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics.
abstract: Cytochrome P450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene product P-glycoprotein (P-gp) are present at high concentrations in villus tip enterocytes of the small intestine and share a significant overlap in substrate specificity. A large body of research both in vitro and in vivo has established metabolism by intestinal CYP3A4 as a major determinant of the systemic bioavailability of orally administered drugs. More recently it has been recognized that drug extrusion by intestinal P-gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A-mediated metabolism. There is relatively little data regarding the effects of CYP3A and P-gp on peptide drugs; however, studies with the cyclic peptide immunosuppresant cyclosporine as well as peptidomimetics such as the HIV-protease inhibitor saquinavir (Invirase) and a new cysteine protease inhibitor K02 (Morpholine-Urea-Phe-Hphe-Vinyl sulfone; Axys Pharmaceuticals) provide some insight into the impact of these systems on the oral absorption of peptides.
authors.affiliation: AvMax Inc., 890 Heinz Avenue, Berkeley, California, 94710 and Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94143-0446, USA. vwacher@worldnet.att.net
authors.forename: V J
authors.initials: VJ
authors.lastname: Wacher
authors.forename: J A
authors.initials: JA
authors.lastname: Silverman
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004151:Dipeptides / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism*; D009025:Morpholines / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010455:Peptides / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004151:Dipeptides; D009025:Morpholines; D010455:Peptides; C111861:ko2 mu-urea-phe-hphe vinylsulfone; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D019258:Saquinavir