Pharmacokinetics of clopidogrel after administration of a high loading dose

Dirk Taubert; Adnan Kastrati; Steffi Harlfinger; Olga Gorchakova; Andreas Lazar; Nicolas von Beckerath; Albert Schömig; Edgar Schömig

doi:10.1160/TH04-02-0105

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(02): 311-316
DOI: 10.1160/TH04-02-0105

Rapid and Short Communication

Schattauer GmbH

Pharmacokinetics of clopidogrel after administration of a high loading dose

Dirk Taubert

¹Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

,

Adnan Kastrati

²Deutsches Herzzentrum München, Munich, Germany

,

Steffi Harlfinger

¹Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

,

Olga Gorchakova

²Deutsches Herzzentrum München, Munich, Germany

,

Andreas Lazar

¹Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

,

Nicolas von Beckerath

²Deutsches Herzzentrum München, Munich, Germany

,

Albert Schömig

²Deutsches Herzzentrum München, Munich, Germany

,

Edgar Schömig

¹Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

› Institutsangaben

Abstract

Summary

The adenosine diphosphate (ADP) receptor P2Y12 blocking agent clopidogrel is clinically proven to be efficient in preventing thrombotic events. However, its therapeutic value is limited by an, as yet poorly explained, interindividual heterogeneity in platelet inhibition. To evaluate possible pharmacokinetic determinants of this response variability, we developed a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantification of unmodified inactive clopidogrel, its inactive carboxyl metabolite, and its active thiol metabolite in plasma. Analyte concentrations and platelet aggregation were assessed in ten healthy volunteers receiving an oral load of 600 mg clopidogrel. Subjects showed marked inter-individual differences in maximal platelet inhibition and in plasma pharmacokinetics. Univariate regression revealed linear correlations between maximal antiplatelet effect and peak plasma concentrations (c_max) of unchanged clopidogrel (r=0.76; p=0.01), of the carboxyl metabolite (r=0.70; p=0.03), and of the thiol metabolite (r=0.73; p=0.02), as well as linear correlations between c_max values of clopidogrel and its metabolites. This indicates that the response variability is predominantly caused by individual differences in clopidogrel absorption and that other factors, such as ADP receptor reactivity or differences in bioactivation of clopidogrel, do not play a major role.

Keywords

Clopidogrel - pharmacokinetics - platelet inhibition - response variability

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