Effect of alcohol on clopidogrel metabolism: Identification of a new alcohol‐dependent metabolic pathway (1141.14)

Abstract

The majority of orally administrated clopidogrel, a platelet aggregation inhibitor, is hydrolyzed by human carboxyesterase‐1 (CES1) to the inactive clopidogrel acid metabolite with the remainder metabolized by CYP450 enzymes into the inactive intermediate, 2‐oxo‐clopidogrel, that is further oxidized to the active thiol metabolite. The objective of this study was to determine the effect of alcohol, a known CES1 inhibitor, on the metabolism of clopidogrel. Clopidogrel metabolism was studied in human recombinant CES1, human liver S9 fractions (HLS9), and in plasma‐carboxylesterase knockout mice. Liquid chromatography/triple quadrupole mass spectrometry (LC‐MS/MS) was utilized for the quantification of clopidogrel and its metabolites. Alcohol‐derived metabolites were identified by product ion scan using LC‐MS/MS. The addition of alcohol resulted in the formation of the transesterified clopidogrel metabolite, ethyl‐clopidogrel in CES1 and HLS9 incubations. Similar to clopidogrel, ethyl‐clopidogrel was metabolized to ethyl‐2‐oxo‐clopidogrel followed by the subsequent oxidation to thiol metabolites in HLS9. Co‐administration of alcohol (3 g/kg) and clopidogrel (25 mg/kg) to plasma‐carboxylesterase knockout mice resulted in a reduced systemic exposure to clopidogrel acid (control AUC0‐8h 39 µg·h/mL versus alcohol AUC0‐8h 20 µg·h/mL) and the formation of transesterified metabolites. Alcohol significantly inhibits the hydrolysis of clopidogrel to clopidogrel acid, and produces transesterified metabolites of clopidogrel, 2‐oxo‐clopidogrel, and the active metabolite.Grant Funding Source: Supported by National Institutes of Health National Institute of General Medical Sciences