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Research ArticleArticle

Comprehensive Evaluation for Substrate Selectivity of Cynomolgus Monkey Cytochrome P450 2C9, a New Efavirenz Oxidase

Shinya Hosaka, Norie Murayama, Masahiro Satsukawa, Shotaro Uehara, Makiko Shimizu, Kazuhide Iwasaki, Shunsuke Iwano, Yasuhiro Uno and Hiroshi Yamazaki
Drug Metabolism and Disposition July 2015, 43 (7) 1119-1122; DOI: https://doi.org/10.1124/dmd.115.063925
Shinya Hosaka
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.)
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Norie Murayama
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.)
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Masahiro Satsukawa
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.)
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Shotaro Uehara
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.)
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Makiko Shimizu
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.)
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Kazuhide Iwasaki
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.)
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Shunsuke Iwano
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.)
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Yasuhiro Uno
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.)
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Hiroshi Yamazaki
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.)
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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.

Footnotes

    • Received February 20, 2015.
    • Accepted May 6, 2015.
  • dx.doi.org/10.1124/ dmd.115.063925.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Novel Monkey CYP2C9 Substrates

Shinya Hosaka, Norie Murayama, Masahiro Satsukawa, Shotaro Uehara, Makiko Shimizu, Kazuhide Iwasaki, Shunsuke Iwano, Yasuhiro Uno and Hiroshi Yamazaki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1119-1122; DOI: https://doi.org/10.1124/dmd.115.063925

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Research ArticleArticle

Novel Monkey CYP2C9 Substrates

Shinya Hosaka, Norie Murayama, Masahiro Satsukawa, Shotaro Uehara, Makiko Shimizu, Kazuhide Iwasaki, Shunsuke Iwano, Yasuhiro Uno and Hiroshi Yamazaki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1119-1122; DOI: https://doi.org/10.1124/dmd.115.063925
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