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Research ArticleArticle

INTERACTIONS OF TWO MAJOR METABOLITES OF PRASUGREL, A THIENOPYRIDINE ANTIPLATELET AGENT, WITH THE CYTOCHROMES P450

Jessica L. Fayer Rehmel, James A. Eckstein, Nagy A. Farid, John B. Heim, Steve C. Kasper, Atsushi Kurihara, Steven A. Wrighton and Barbara J. Ring
Drug Metabolism and Disposition April 2006, 34 (4) 600-607; DOI: https://doi.org/10.1124/dmd.105.007989
Jessica L. Fayer Rehmel
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James A. Eckstein
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Nagy A. Farid
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John B. Heim
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Steve C. Kasper
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Atsushi Kurihara
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Steven A. Wrighton
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Barbara J. Ring
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Abstract

The biotransformation of prasugrel to R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid) involves rapid deesterification to R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone) followed by cytochrome P450 (P450)-mediated formation of R-138727, the metabolite responsible for platelet aggregation. For identification of the P450s responsible for the formation of the active metabolite, the current studies were conducted with R-95913 as the substrate. Incubations required supplementation with reduced glutathione. Hyperbolic kinetics (Km 21–30 μM), consistent with a single enzyme predominating, were observed after incubations with human liver microsomes. Correlation analyses revealed a strong relationship between R-138727 formation and CYP3A-mediated midazolam 1′-hydroxylation (r2 = 0.98; p < 0.001) in a bank of characterized human liver microsomal samples. The human lymphoblast-expressed enzymes capable of forming R-138727, in rank order of rates, were CYP3A4>CYP2B6>CYP2C19≈CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, whereas inhibitors of CYP2C9 (sulfaphenazole) and CYP2C19 (omeprazole) did not. Scaling of in vitro intrinsic clearance values from expressed enzymes to the whole liver using a relative abundance approach indicated that either CYP3A4 alone or CYP3A4 and CYP2B6 are the major contributors to R-138727 formation. R-95913 and R-138727 were also examined for their ability to inhibit metabolism mediated by five P450s. R-138727 did not inhibit the P450s tested. In vitro, R-95913 inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A, with Ki values ranging from 7.2 μM to 82 μM, but did not inhibit CYP1A2. These Ki values exceed circulating concentrations in humans by 3.8- to 43-fold. Therefore, neither R-95913 nor R-138727 is expected to substantially inhibit the P450-mediated metabolism of coadministered drugs.

Footnotes

  • A portion of this work was presented at the 7th International ISSX Meeting, Vancouver, BC, Canada, 2004 and was published in abstract form in Drug Metab Rev36 (Suppl 1): 342.

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

  • doi:10.1124/dmd.105.007989.

  • ABBREVIATIONS: prasugrel, (±)-2-[2-acetyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone hydrochloride; 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; P450, cytochrome P450; LC/MS/MS, liquid chromatography/tandem mass spectrometry; GSH, reduced glutathione; BMAP, 2-bromo-3′-methoxyacetophenone; mAb, monoclonal antibody; HPLC, high-performance liquid chromatography; CLint, intrinsic clearance.

    • Received October 31, 2005.
    • Accepted January 11, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

INTERACTIONS OF TWO MAJOR METABOLITES OF PRASUGREL, A THIENOPYRIDINE ANTIPLATELET AGENT, WITH THE CYTOCHROMES P450

Jessica L. Fayer Rehmel, James A. Eckstein, Nagy A. Farid, John B. Heim, Steve C. Kasper, Atsushi Kurihara, Steven A. Wrighton and Barbara J. Ring
Drug Metabolism and Disposition April 1, 2006, 34 (4) 600-607; DOI: https://doi.org/10.1124/dmd.105.007989

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Research ArticleArticle

INTERACTIONS OF TWO MAJOR METABOLITES OF PRASUGREL, A THIENOPYRIDINE ANTIPLATELET AGENT, WITH THE CYTOCHROMES P450

Jessica L. Fayer Rehmel, James A. Eckstein, Nagy A. Farid, John B. Heim, Steve C. Kasper, Atsushi Kurihara, Steven A. Wrighton and Barbara J. Ring
Drug Metabolism and Disposition April 1, 2006, 34 (4) 600-607; DOI: https://doi.org/10.1124/dmd.105.007989
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