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Research ArticleArticle

Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 530348 (Vorapaxar), a Potent Oral Thrombin Protease-Activated Receptor 1 Antagonist

Anima Ghosal, Xiaowen Lu, Natalia Penner, Lan Gao, Ragu Ramanathan, Swapan K. Chowdhury, Narendra S. Kishnani and Kevin B. Alton
Drug Metabolism and Disposition January 2011, 39 (1) 30-38; DOI: https://doi.org/10.1124/dmd.110.035493
Anima Ghosal
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Xiaowen Lu
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Natalia Penner
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Lan Gao
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Ragu Ramanathan
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Swapan K. Chowdhury
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Narendra S. Kishnani
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Kevin B. Alton
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, New Jersey
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Abstract

Vorapaxar (SCH 530348), a potent oral thrombin protease-activated receptor 1 antagonist, is being developed as an antiplatelet agent for patients with established vascular disease. The objective of this study was to identify the human liver cytochrome P450 (P450) enzyme(s) responsible for the metabolism of SCH 530348. Human liver microsomes metabolized SCH 530348 to M19, an amine metabolite formed via carbamate cleavage, and M20 (monohydroxy-SCH 530348). Recombinant human CYP3A4 exhibited the most activity (11.5% profiled radioactivity) for the formation of M19, followed by markedly less substrate conversion with CYP1A1 and CYP2C19. Trace levels of M19, a major excreted human metabolite, were detected with CYP1A2, CYP3A5, and CYP4F3A. Formation of M19 by human liver microsomes was inhibited 89% by ketoconazole (IC50, 0.73 μM), 34% by tranylcypromine, and 89% by anti-CYP3A4 monoclonal antibody. There was a significant correlation between the rate of M19 formation and midazolam 1′-hydroxylation (r = 0.75) or M19 formation and testosterone 6β-hydroxylation (r = 0.92). The results of screening, inhibition, and correlation studies confirmed that CYP3A4 is the major P450 enzyme responsible for M19 formation from SCH 530348. In contrast, formation of M20, a major circulating human metabolite at steady state, was primarily catalyzed by CYP3A4 and CYP2J2. M20 is pharmacologically equipotent to SCH 530348, whereas M19 is an inactive metabolite. Formation of M20 by human liver microsomes was inhibited 89% by ketoconazole, 75% by astemizole (a CYP2J2 inhibitor), and 43% by CYP3A4 monoclonal antibody. These results suggest that CYP3A4 and CYP2J2 are both involved in the formation of M20 metabolite.

Footnotes

    • Received July 14, 2010.
    • Accepted October 6, 2010.
  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035493.

  • ABBREVIATIONS:

    SCH 530348
    ethyl[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]-dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamate
    PAR-1
    protease-activated receptor 1
    MI
    myocardial infarction
    P450
    cytochrome P450
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    HLMs
    human liver microsomes
    FSA
    flow scintillation analyzer.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 530348 (Vorapaxar), a Potent Oral Thrombin Protease-Activated Receptor 1 Antagonist

Anima Ghosal, Xiaowen Lu, Natalia Penner, Lan Gao, Ragu Ramanathan, Swapan K. Chowdhury, Narendra S. Kishnani and Kevin B. Alton
Drug Metabolism and Disposition January 1, 2011, 39 (1) 30-38; DOI: https://doi.org/10.1124/dmd.110.035493

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Research ArticleArticle

Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 530348 (Vorapaxar), a Potent Oral Thrombin Protease-Activated Receptor 1 Antagonist

Anima Ghosal, Xiaowen Lu, Natalia Penner, Lan Gao, Ragu Ramanathan, Swapan K. Chowdhury, Narendra S. Kishnani and Kevin B. Alton
Drug Metabolism and Disposition January 1, 2011, 39 (1) 30-38; DOI: https://doi.org/10.1124/dmd.110.035493
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