title: Clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin-converting enzyme inhibitors after myocardial infarction: a proof-of-concept study.
abstract: Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting enzyme inhibitors (ACEIs) are also metabolized by this enzyme. We examined the effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmacoepidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70,934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients cotreated with or without clopidogrel were 1.10 (95% confidence interval (CI): 0.97-1.25, P = 0.124) and 0.90 (95% CI: 0.81-0.99, P = 0.025), respectively, as compared with patients who did not receive ACEIs. This difference was statistically significant (P = 0.002). We conclude that cotreatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmacoepidemiological studies may be a useful paradigm for assessment of drug-drug interactions.
authors.affiliation: Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.
authors.forename: K E
authors.initials: KE
authors.lastname: Kristensen
authors.affiliation: Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark [2] National Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: G H
authors.initials: GH
authors.lastname: Gislason
authors.affiliation: Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Torp-Pedersen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, Denmark.
authors.forename: H B
authors.initials: HB
authors.lastname: Rasmussen
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Markowitz
authors.affiliation: Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.
authors.forename: P R
authors.initials: PR
authors.lastname: Hansen
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001711:Biotransformation; D002265:Carboxylic Ester Hydrolases / Q000502:physiology; D000077144:Clopidogrel; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D012306:Risk; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D013988:Ticlopidine