title: Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein.
abstract: The role of the major drug-metabolizing cytochrome P450 (CYP) enzymes as well as P-glycoprotein (PGP) was investigated in the disposition of ketobemidone in vitro. Formation of norketobemidone from ketobemidone was studied and compared with the activities of 11 major CYP enzymes in human liver microsomes. The formation of norketobemidone from ketobemidone (1 microM) correlated best with CYP2C9 activity, measured as losartan oxidation (rs = 0.82, n = 19, p < 0.001), but there was also a strong correlation with CYP3A4 activity. Additionally, a good correlation was observed with CYP2C19, CYP2C8 and CYP2B6 at a ketobemidone concentration of 50 microM. Inhibition studies confirmed the involvement of CYP2C9 and CTP3A4 in the formation of norketobemidone. The formation rate of norketobemidone was three times higher in the CYP2C9*1*1 genotype group compared with the CYP2C9*1*2, CYP2C9*1*3 and CYP2C9*3*3 genotypes (p < 0.01). Treatment with verapamil as a PGP inhibitor did not affect the transport of ketobemidone in Caco-2 cells, indicating that PGP is not involved. The data suggest that CYP2C9 and CYP3A4 play a major role in the formation of norketobemidone at clinically relevant concentrations.
authors.affiliation: Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Yasar
authors.forename: A
authors.initials: A
authors.lastname: Annas
authors.forename: J-O
authors.initials: JO
authors.lastname: Svensson
authors.forename: L
authors.initials: L
authors.lastname: Lazorova
authors.forename: P
authors.initials: P
authors.lastname: Artursson
authors.forename: A
authors.initials: A
authors.lastname: Al-Shurbaji
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D001692:Biological Transport; D018938:Caco-2 Cells; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007540:Isonipecotic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008614:Meperidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008862:Microsomes, Liver; D016297:Mutagenesis, Site-Directed; D010636:Phenols / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity; D013426:Sulfaphenazole / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D065607:Cytochrome P-450 Enzyme Inhibitors; D007540:Isonipecotic Acids; D010636:Phenols; D013426:Sulfaphenazole; C011044:norketobemidone; D003577:Cytochrome P-450 Enzyme System; D008614:Meperidine; D014217:Troleandomycin; D014700:Verapamil; C012394:ketobemidone; D007654:Ketoconazole