title: Identification of cytochromes P450 involved in human liver microsomal metabolism of ecabapide, a prokinetic agent.
abstract: 1. In vitro studies identified the hepatic cytochrome P450 (CYP) enzyme(s) involved in the major metabolism of ecabapide in human. 2. Ecabapide mainly underwent N-dealkylation to form M1 and 6-hydroxylation of the benzamide moiety to form M6. 3. The rates of formation of the major metabolites M1 and M6 were significantly correlated with CYP3A-selective testosterone 6beta-hydroxylase activities in 14 different human liver microsomes. The formation of both metabolites was markedly decreased by ketoconazole, miconazole or troleandomycin (TAO), CYP3A-selective inhibitors, and also was inhibited by anti-CYP3A antibodies. 4. These results strongly indicate that CYP3A is the predominant isozyme responsible for the major metabolism of ecabapide in human liver microsomes. 5. Marginal inhibition of the formation of M1 and M6 by nifedipine, a substrate of CYP3A with a Ki > 100 microM, suggested that nifedipne has a limited potential to inhibit the major metabolic pathways of ecabapide.
authors.affiliation: Drug Metabolism & Analytical Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan. fujim28k@daiichipharm.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Fujimaki
authors.forename: N
authors.initials: N
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Inaba
mesh_terms: D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D013379:Substrate Specificity; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000897:Anti-Ulcer Agents; D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C058308:ecabapide; D009249:NADP; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D019363:Cytochrome P-450 CYP1A1; D007654:Ketoconazole