Pharmacokinetics of clopidogrel after administration of a high loading dose
Dirk Taubert(1), Adnan Kastrati(2), Steffi Harlfinger(1),Olga Gorchakova(2), Andreas Lazar(1), Nicolas von Beckerath(2), Albert Schömig(2), Edgar Schömig(1)
(1)Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany (2)Deutsches Herzzentrum München, Munich, Germany
Summary The adenosine diphosphate (ADP) receptor P2Y12 blockingagent clopidogrel is clinically proven to be efficient in preventingthrombotic events. However, its therapeutic value is limitedby an, as yet poorly explained, interindividual heterogeneity inplatelet inhibition.To evaluate possible pharmacokinetic determinantsof this response variability, we developed a sensitiveand specific liquid chromatography tandem mass spectrometry(LC-MS/MS) assay for quantification of unmodified inactive clopidogrel,its inactive carboxyl metabolite, and its active thiolmetabolite in plasma. Analyte concentrations and plateletaggregation were assessed in ten healthy volunteers receiving anoral load of 600 mg clopidogrel. Subjects showed marked inter-individual differences in maximal platelet inhibition and in plasmapharmacokinetics. Univariate regression revealed linear correlationsbetween maximal antiplatelet effect and peak plasmaconcentrations (cmax) of unchanged clopidogrel (r=0.76;p=0.01), of the carboxyl metabolite (r=0.70; p=0.03), and of thethiol metabolite (r=0.73; p=0.02), as well as linear correlationsbetween cmax values of clopidogrel and its metabolites. Thisindicates that the response variability is predominantly causedby individual differences in clopidogrel absorption and thatother factors, such as ADP receptor reactivity or differences inbioactivation of clopidogrel, do not play a major role.