Key result
Alcohol significantly inhibited clopidogrel hydrolysis in vitro and increased clopidogrel AUC by 91% and its active metabolite H4 AUC by 22% in Es1e mice.
Why the study?
Most clopidogrel research has focused on hepatic CYP450 metabolism, despite 85-90% of clopidogrel being hydrolyzed by human carboxylesterase-1 (CES1).
Does alcohol inhibit CES1 and alter clopidogrel metabolism in vitro and in a mouse model?
Does alcohol inhibit CES1 and alter clopidogrel metabolism in vitro and in a mouse model?
Alcohol inhibits CES1-mediated clopidogrel metabolism, increasing exposure to clopidogrel and its active metabolite in a preclinical model.
Alcohol may increase clopidogrel exposure via CES1 inhibition; leaves open clinical relevance and human translation.
Clopidogrel is widely prescribed in patients with cardiovascular disease. Most research has focused on the role of hepatic CYP450 metabolism as the primary source of response variability despite 85–90% of clopidogrel being hydrolyzed by human carboxylesterase-1 (CES1).The purpose of this study is to determine the effects of the known CES1 inhibitor alcohol on clopidogrel metabolism: (1) in vitro in human recombinant CES1 and human liver S9 (HLS9) fractions and (2) in a plasma carboxylesterase deficient mouse (Es1e) strain administered 25 mg/kg oral clopidogrel alone and with 3 g/kg alcohol.Alcohol significantly inhibited the hydrolysis of clopidogrel (IC50 161 mM) and 2-oxo-clopidogrel (IC50 6 mM). In HLS9, alcohol treatment formed ethylated metabolites via transesterification and an increased formation of the H4 active metabolite. These results were replicated in Es1e mice as alcohol increased clopidogrel (91%) and H4 (22%) AUC and reduced formation of the clopidogrel (48%) and 2-oxo-clopidogrel (42%) carboxylate metabolites.Clopidogrel metabolism is highly sensitive to alterations in CES1 activity. The Es1e mouse may represent a suitable model of human CES1 drug metabolism that can be used to rapidly assess how alterations in CES1 function impact the disposition of substrate drugs.
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Laizure et al. (2019) studied this question. Alcohol vs. Clopidogrel alone was evaluated on Clopidogrel metabolism (hydrolysis and AUC of clopidogrel and metabolites). Alcohol significantly inhibited clopidogrel hydrolysis in vitro and increased clopidogrel AUC by 91% and its active metabolite H4 AUC by 22% in Es1e mice.
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