title: Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans.
abstract: Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-∞ ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-∞ of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: E K
authors.initials: EK
authors.lastname: Tarkiainen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: M T
authors.initials: MT
authors.lastname: Holmberg
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Tornio
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Neuvonen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Niemi
mesh_terms: D000328:Adult; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D000077144:Clopidogrel; D005260:Female; D005838:Genotype; D006801:Humans; D006868:Hydrolysis; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D013988:Ticlopidine