Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

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Author(s)

    • Wang Xinwen Wang Xinwen
    • Department of Clinical, Social, and Administrative Sciences, University of Michigan|The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University

Abstract

Patients with coronary artery disease often receive concurrent treatment with clopidogrel and a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor medication. Accordingly, potential drug–drug interactions associated with the concomitant use of these agents present an area of concern. Both CYP enzymes and carboxylesterase 1 (CES1) are involved in the metabolism of clopidogrel, while CES1 is believed to be the enzyme responsible for the activation of simvastatin. Some <i>in vitro</i> studies have suggested that simvastatin could attenuate clopidogrel activation <i>via</i> inhibiting CYP3A activity. However, these findings have not found support in several recently published clinical investigations. The present study addresses these inconsistencies by exploring the potential role of CES1 in the metabolism of clopidogrel and simvastatin. Our <i>in vitro</i> human liver s9 fraction incubation study demonstrated that simvastatin significantly enhanced the formation of the intermediate metabolite 2-oxo-clopidogrel, and inhibited the CES1-mediated hydrolysis of clopidogrel, 2-oxo-clopidogrel, and the active metabolite. However, the production of the active metabolite remained unchanged. Conversely, clopidogrel was not found to influence the CES1 mediated hydrolysis (activation) of simvastatin. Moreover, we provided evidence that CES1 is not an efficient enzyme for catalyzing simvastatin activation. In summary, the inhibitory effect of simvastatin on the hydrolysis of clopidogrel and its principal metabolites may have offset the influence of simvastatin-mediated inhibition of CYP3A, and permitted the unaltered formation of the clopidogrel active metabolite. These data help explain the conflicting accounts in previous reports regarding clopidogrel and simvastatin interactions by taking into consideration CES1; they suggest that the interactions are unlikely to significantly influence clinical outcomes.

Journal

  • Biological and Pharmaceutical Bulletin

    Biological and Pharmaceutical Bulletin 38(2), 292-297, 2015

    The Pharmaceutical Society of Japan

Codes

  • NII Article ID (NAID)
    130004872259
  • NII NACSIS-CAT ID (NCID)
    AA10885497
  • Text Lang
    ENG
  • ISSN
    0918-6158
  • NDL Article ID
    026069931
  • NDL Call No.
    Z53-V41
  • Data Source
    NDL  J-STAGE 
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