Inhibition of carboxylesterase-1 alters clopidogrel metabolism and disposition.
- Resource Type
- Article
- Authors
- Laizure, S. Casey; Hu, Zhe-Yi; Potter, Philip M.; Parker, Robert B.
- Source
- Xenobiotica. Mar2020, Vol. 50 Issue 3, p245-251. 7p.
- Subject
- *ALCOHOL
*PRASUGREL
*METABOLISM
*DRUG metabolism
*CLOPIDOGREL
*TRANSESTERIFICATION
- Language
- ISSN
- 0049-8254
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. [ABSTRACT FROM AUTHOR]