title: Comprehensive Evaluation for Substrate Selectivity of Cynomolgus Monkey Cytochrome P450 2C9, a New Efavirenz Oxidase.
abstract: Cynomolgus monkeys are widely used as primate models in preclinical studies, because of their evolutionary closeness to humans. In humans, the cytochrome P450 (P450) 2C enzymes are important drug-metabolizing enzymes and highly expressed in livers. The CYP2C enzymes, including CYP2C9, are also expressed abundantly in cynomolgus monkey liver and metabolize some endogenous and exogenous substances like testosterone, S-mephenytoin, and diclofenac. However, comprehensive evaluation regarding substrate specificity of monkey CYP2C9 has not been conducted. In the present study, 89 commercially available drugs were examined to find potential monkey CYP2C9 substrates. Among the compounds screened, 20 drugs were metabolized by monkey CYP2C9 at a relatively high rates. Seventeen of these compounds were substrates or inhibitors of human CYP2C9 or CYP2C19, whereas three drugs were not, indicating that substrate specificity of monkey CYP2C9 resembled those of human CYP2C9 or CYP2C19, with some differences in substrate specificities. Although efavirenz is known as a marker substrate for human CYP2B6, efavirenz was not oxidized by CYP2B6 but by CYP2C9 in monkeys. Liquid chromatography-mass spectrometry analysis revealed that monkey CYP2C9 and human CYP2B6 formed the same mono- and di-oxidized metabolites of efavirenz at 8 and 14 positions. These results suggest that the efavirenz 8-oxidation could be one of the selective markers for cynomolgus monkey CYP2C9 among the major three CYP2C enzymes tested. Therefore, monkey CYP2C9 has the possibility of contributing to limited specific differences in drug oxidative metabolism between cynomolgus monkeys and humans.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Shinya
authors.initials: S
authors.lastname: Hosaka
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satsukawa
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Iwano
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (S.H., N.M., M.Shi., S.U., S.I., H.Y.); Pharmacokinetics and Safety Research Department, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (S.H., M.Sa.); Novartis Pharma K.K., Tokyo, Japan (S.I.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.I., Y.U.) hyamazak@ac.shoyaku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D048588:Benzoxazines / Q000378:metabolism*; D003521:Cyclopropanes; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D065729:Cytochrome P-450 CYP2C9; C098320:efavirenz