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Does Clopidogrel Decrease the Efficacy of Carboxylesterase‐1 Prodrugs?

It has previously been reported that clopidogrel is a potent inhibitor of the carboxylesterase‐1 (CES1) mediated hydrolysis of oseltamivir to its active metabolite based on in vitro inhibition studies. However, clopidogrel undergoes extensive first‐pass hepatic metabolism resulting in 85% of the dose being metabolized to clopidogrel carboxylate prior to reaching the systemic circulation. Thus, despite its potency as an inhibitor of CES1 enzyme activity, it is unlikely to affect the formation of oseltamivir or any other CES1‐substrate prodrug due to the low level of systemic exposure. We studied the inhibition of clopidogrel and its major metabolite, clopidogrel carboxylate, on another CES1‐substrate prodrug used in the treatment of multiple sclerosis, dimethyl fumarate. Our finding corroborates the previous study demonstrating potent inhibition of CES1 enzyme activity by clopidogrel, but also demonstrated a similar potency in the inhibition of enzyme activity by its major metabolite, clopidogrel carboxylate. In human recombinant CES1 enzyme 50 μM of clopidogrel or clopidogrel carboxylate inhibited the CES1‐mediated hydrolysis of dimethyl fumarate to monomethyl fumarate by 90%. Given that the maximum plasma concentration of the clopidogrel carboxylate metabolite is over 1000‐fold greater than clopidogrel after normal therapeutic doses, the primary inhibition of CES1 enzyme activity will be due to clopidogrel carboxylate and not clopidogrel. Furthermore, the maximum concentration of the clopidogrel carboxylate metabolite reported after a 600 mg clopidogrel loading dose was 71.4 μM, which would be in excess of the concentration required to achieve a 90% reduction in CES1 enzyme activity. Therapeutic dosing with clopidogrel is likely to inhibit the formation of the active metabolite of CES1‐substrate prodrugs resulting in therapeutic failure.