title: Effect of cyclosporine and tacrolimus on cytochrome p450 activities in human liver microsomes.
abstract: The effects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 muM, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K(i)) of 1.42 and 0.36 muM, respectively. In addition, 20 muM cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29% and 30%, respectively. These results suggest that tacrolimus would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory effect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the differences in the inhibition potential. Obvious substrate-dependent effects on CYP3A4-inhibition potential were not observed.
authors.affiliation: Post Marketing Product Development, Astellas Pharma Inc., Chuo-ku, Osaka, Japan. toshiro.niwa@jp.astellas.com
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Miho
authors.initials: M
authors.lastname: Saito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Shiraga
authors.forename: Akira
authors.initials: A
authors.lastname: Takagi
mesh_terms: D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus