Inhibition of carboxylesterase-1 alters clopidogrel metabolism and disposition

Steven Laizure, Zhe Yi Hu, Philip M. Potter, Robert Parker

Research output: Contribution to journalArticle

Abstract

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 (Es1 e ) strain administered 25 mg/kg oral clopidogrel alone and with 3 g/kg alcohol. Alcohol significantly inhibited the hydrolysis of clopidogrel (IC 50 161 mM) and 2-oxo-clopidogrel (IC 50 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 Es1 e 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 Es1 e 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.

Original languageEnglish (US)
JournalXenobiotica
DOIs
StatePublished - Jan 1 2019

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clopidogrel
Enzyme inhibition
Carboxylesterase
Metabolism
Alcohols
Metabolites
Liver
Transesterification
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

Inhibition of carboxylesterase-1 alters clopidogrel metabolism and disposition. / Laizure, Steven; Hu, Zhe Yi; Potter, Philip M.; Parker, Robert.

In: Xenobiotica, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "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 (Es1 e ) strain administered 25 mg/kg oral clopidogrel alone and with 3 g/kg alcohol. Alcohol significantly inhibited the hydrolysis of clopidogrel (IC 50 161 mM) and 2-oxo-clopidogrel (IC 50 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 Es1 e 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 Es1 e 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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