title: Determination of clopidogrel main metabolite in plasma: a useful tool for monitoring therapy?
abstract: This study was performed to determine whether analysis of clopidogrel and its main carboxylic acid metabolite in plasma provides additional information about the wide variability of platelet aggregation inhibition in clopidogrel-treated patients with peripheral arterial occlusive disease. Consecutive outpatients (n = 56) with stable peripheral arterial occlusive disease treated with 75 mg clopidogrel daily, without co-administration of aspirin, were investigated. With use of a standardized questionnaire, the time of drug intake was documented. Blood sampling was performed within 24 hours after the most recent drug intake. Platelet function was measured by optical aggregometry using adenosine diphosphate (ADP) (2 mumol/L) as the agonist. Plasma concentrations of clopidogrel and its main metabolite, clopidogrel carboxylic acid, were quantitated using high-performance liquid chromatography analysis coupled to mass spectrometry. In 95% (53/56) of patients, clopidogrel carboxylic acid was detected. In 40% (22/56) of patients, the ADP-induced aggregation response was within the normal range despite clopidogrel treatment. In 14% (3/22) of these patients, neither clopidogrel nor its main metabolite could be detected. Two of these patients agreed to ingest 75 mg/d clopidogrel under observation and to undergo blood sampling after 2, 12, and 24 hours. Clopidogrel carboxylic acid and a significant inhibition of platelet aggregation were detected even after 24 hours in both patients, confirming noncompliance as the reason for the lack of inhibition of ADP-induced platelet aggregation observed in the initial measurements. In the subgroup of patients who had taken clopidogrel within 4 hours before blood sampling, a large range of carboxylic acid concentrations was detected, indicating a high variability of drug metabolism among patients. In conclusion, determining clopidogrel metabolite plasma concentrations could be a useful tool for identifying poor compliance and variable metabolism in clopidogrel-treated patients. Nevertheless, in the majority of clopidogrel-treated patients, the variability of platelet response is not caused by noncompliance.
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine, University Hospital Frankfurt/Main, Germany. helenmani@gmx.de
authors.forename: Helen
authors.initials: H
authors.lastname: Mani
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Toennes
authors.forename: Birgit
authors.initials: B
authors.lastname: Linnemann
authors.forename: Dorota A
authors.initials: DA
authors.lastname: Urbanek
authors.forename: Jan
authors.initials: J
authors.lastname: Schwonberg
authors.forename: Gerold F
authors.initials: GF
authors.lastname: Kauert
authors.forename: Edelgard
authors.initials: E
authors.lastname: Lindhoff-Last
mesh_terms: D000368:Aged; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D016491:Peripheral Vascular Diseases / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; C528640:clopidogrel carboxylic acid; D000077144:Clopidogrel; D013988:Ticlopidine