Metabolism of Selegiline Hydrochloride, a Selective Monoamine B-type Inhibitor, in Human Liver Microsomes

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  • KAMADA Takahiro
    Institute of Research and Development, Fujimoto Pharmaceutical Corporation Department of Chemical Biology, Osaka City University Medical School
  • OHDE Hironori
    Institute of Research and Development, Fujimoto Pharmaceutical Corporation
  • FUNAE Yoshihiko
    Department of Chemical Biology, Osaka City University Medical School
  • MORIMOTO Kazuhiko
    Institute of Research and Development, Fujimoto Pharmaceutical Corporation
  • HIROI Toyoko
    Department of Chemical Biology, Osaka City University Medical School
  • IMAOKA Susumu
    Department of Chemical Biology, Osaka City University Medical School
  • CHOW Toshio
    Department of Chemical Biology, Osaka City University Medical School

書誌事項

公開日
2002
DOI
  • 10.2133/dmpk.17.199
公開者
日本薬物動態学会

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説明

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (Km=21.4 μM) and N-demethylation (Km=25.2 μM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4′-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19.<br>   In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.<br>

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