title: Investigation of drug-drug interactions between clopidogrel and fluoxetine.
abstract: Drug-drug interactions may contribute to the variability of the response of clopidogrel. Several hypotheses have been proposed concerning the potential modification of clopidogrel pharmacokinetics and pharmacodynamics by fluoxetine. This open-label crossover study assessed the effect of fluoxetine on the pharmacological activity of clopidogrel in healthy volunteers. Eight healthy male volunteers received a single 600-mg loading dose of clopidogrel followed by 20 mg of fluoxetine on 4 days and then 20 mg of fluoxetine plus 600 mg of clopidogrel on the fifth day. Eleven blood samples were withdrawn after clopidogrel administration to determine plasma concentrations of clopidogrel active metabolite (CAM) and platelet function. Platelet aggregation was measured by light transmittance aggregometry (LTA) and platelet reactivity index by flow cytometric vasodilator-stimulated phosphoprotein (VASP) analysis. The areas under the curve and maximum plasma concentrations of CAM were, respectively, 20.6 and 25.3% lower after co-administration of fluoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values in the presence of 5 μM and 10 μM adenosine diphosphate, measured by LTA, were, respectively, 13.9 and 22.4% lower after fluoxetine co-administration. The platelet reactivity index measured by the flow cytometric VASP method was 36.8% lower when clopidogrel was administered in conjunction with fluoxetine.
authors: Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, F-42055, Saint-Etienne, France; Université de Lyon, F-42023, Saint-Etienne, France; Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, F-42023, Saint-Etienne, France.
authors: Xavier
authors: X
authors: Delavenne
authors: Marion
authors: M
authors: Magnin
authors: Thierry
authors: T
authors: Basset
authors: Michele
authors: M
authors: Piot
authors: Nora
authors: N
authors: Mallouk
authors: Denis
authors: D
authors: Ressnikoff
authors: Arnauld
authors: A
authors: Garcin
authors: Silvy
authors: S
authors: Laporte
authors: Pierre
authors: P
authors: Garnier
authors: Patrick
authors: P
authors: Mismetti
mesh_terms: D000244:Adenosine Diphosphate / Q000008:administration & dosage / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004347:Drug Interactions; D005434:Flow Cytometry; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010979:Platelet Function Tests; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000244:Adenosine Diphosphate; D015815:Cell Adhesion Molecules; D000077144:Clopidogrel; D005473:Fluoxetine; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; D013988:Ticlopidine; D000098662:Vasodilator-Stimulated Phosphoprotein
keywords: clopidogrel resistance; drug-drug interaction; fluoxetine; platelet pharmacology