title: Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P4503A4.
abstract: It has been suggested that cytochrome P450 3A4 (CYP3A4) and MDR1 P-glycoprotein (P-gp) act synergistically to limit the bioavailability of orally administered agents. In order to determine the relative role of these proteins, it is essential to identify a selective inhibitor for either P-gp or CYP3A4. In the present investigation, comparative studies were performed to examine the effect of inhibitors on the function of these proteins. The IC50of P-gp function, determined by examining the inhibition of the transcellular transport of vinblastine across Caco-2 monolayers, was in the order PSC833 << ketoconazole, verapamil << N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl)methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide (L-754,394). In contrast, the IC50of CYP3A4 function, determined by examining the inhibition of the metabolism of midazolam by intestinal and liver microsomes, was in the order L-754,384 < ketoconazole << PSC 833 and verapamil. The ratio of IC50for P-gp to that for CYP3A4 was more than 200 for L-754,394, 60 ~ 150 for ketoconazole, 1.5 for verapamil, and 0.05 for PSC 833. Collectively, it was demonstrated that PSC 833 and L-754,394 can be used as selective inhibitors of P-gp and CYP3A4, respectively.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Achira
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018938:Caco-2 Cells; D003524:Cyclosporins / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007421:Intestine, Small / Q000378:metabolism / Q000648:ultrastructure; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008861:Microsomes / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007189:Indans; C094644:L 754394; D010879:Piperazines; D014747:Vinblastine; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C070272:valspodar; D008874:Midazolam; D007654:Ketoconazole