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Research ArticleArticle

Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Yumi Nishiya, Katsunobu Hagihara, Takashi Ito, Masami Tajima, Shin-ichi Miura, Atsushi Kurihara, Nagy A. Farid and Toshihiko Ikeda
Drug Metabolism and Disposition March 2009, 37 (3) 589-593; DOI: https://doi.org/10.1124/dmd.108.022988
Yumi Nishiya
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Katsunobu Hagihara
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Takashi Ito
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Masami Tajima
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Shin-ichi Miura
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Atsushi Kurihara
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Nagy A. Farid
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Toshihiko Ikeda
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Abstract

Mechanism-based inhibition of CYP2B6 in human liver microsomes by thienopyridine antiplatelet agents ticlopidine and clopidogrel and the thiolactone metabolites of those two agents plus that of prasugrel were investigated by determining the time- and concentration-dependent inhibition of the activity of bupropion hydroxylase as the typical CYP2B6 activity. By comparing the ratios of kinact (maximal inactivation rate constant)/KI (the inactivator concentration producing a half-maximal rate of inactivation), it was found that the thiolactone metabolite of prasugrel is 10- and 22-fold less potent, respectively, in the mechanism-based inhibition of CYP2B6 than ticlopidine and clopidogrel. The kinact/KI ratio of the thiolactone metabolite of ticlopidine was comparable with that of the parent compound, whereas this ratio for the thiolactone metabolite of clopidogrel was significantly smaller than that of clopidogrel. In conclusion, ticlopidine, its thiolactone metabolite, and clopidogrel were more potent mechanism-based inhibitors of CYP2B6 than the thiolactone metabolite of prasugrel.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022988.

  • ABBREVIATIONS: prasugrel, (±)-2-[2-acetyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone; P450, cytochrome P450; R-95913, 2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone; R-138727, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid.

    • Received June 21, 2008.
    • Accepted November 25, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (3)
Drug Metabolism and Disposition
Vol. 37, Issue 3
1 Mar 2009
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Research ArticleArticle

Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Yumi Nishiya, Katsunobu Hagihara, Takashi Ito, Masami Tajima, Shin-ichi Miura, Atsushi Kurihara, Nagy A. Farid and Toshihiko Ikeda
Drug Metabolism and Disposition March 1, 2009, 37 (3) 589-593; DOI: https://doi.org/10.1124/dmd.108.022988

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Research ArticleArticle

Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Yumi Nishiya, Katsunobu Hagihara, Takashi Ito, Masami Tajima, Shin-ichi Miura, Atsushi Kurihara, Nagy A. Farid and Toshihiko Ikeda
Drug Metabolism and Disposition March 1, 2009, 37 (3) 589-593; DOI: https://doi.org/10.1124/dmd.108.022988
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