Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

Abstract

Background and ObjectiveApproximately 5–40 % of patients treated with clopidogrel do not display an adequate antiplatelet response. Clopidogrel resistance may be caused by insufficient drug absorption or impaired metabolic activation of the drug. The aim of this study was to evaluate the pharmacokinetics of clopidogrel and its metabolites in plasma samples from patients treated with high and low doses of clopidogrel, to obtain a possible explanation for antiplatelet resistance.MethodsThe study included patients receiving either a single 300 mg loading dose of clopidogrel (n = 17) or a 75 mg dose (n = 45) for at least 7 days before sample collection. The concentrations of clopidogrel and its metabolites—the inactive H3 and the pharmacologically active H4 isomers of the thiol metabolite and the inactive carboxylic acid metabolite—in plasma samples (stabilized with 2-bromo-3′-methoxyacetophenone) from three patients after 300 mg and from 41 patients after 75 mg of the drug were determined using a validated high-performance liquid chromatography method with tandem mass spectrometry. The non-stabilized samples from the remaining patients were analysed using a validated capillary electrophoresis method. The calculated concentrations were used to determine the pharmacokinetic parameters of the analytes. The pharmacodynamic response to clopidogrel treatment, expressed as adenosine diphosphate-induced platelet aggregation, was measured using a Multiplate analyser.ResultsThe pharmacokinetic parameter values for the H3 and H4 isomers determined in the studied group of patients treated with clopidogrel 75 mg (maximum plasma concentration [Cmax] 5.29 ± 5.54 and 7.13 ± 6.32 ng/mL for H3 and H4, respectively; area under the plasma concentration-time curve from time zero to time t [AUCt] 7.37 ± 6.71 and 11.30 ± 9.58 ng·h/mL for H3 and H4, respectively) were lower than those reported in healthy volunteers, according to the literature data. Platelet aggregation measured with a Multiplate analyser ranged between 37 and 747 AU·min. A significant correlation was found between the Cmax of the active H4 isomer and platelet aggregation (p = 0.025).ConclusionThe Cmax of the active H4 isomer and platelet aggregation measured by the Multiplate analyser may serve as markers of the patient response to clopidogrel therapy.

Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel

“…Because of the different catalytic efficiencies of the P450 isoforms and TMT in the formation and S-methylation of H3 and H4, determining the exposure and pharmacokinetic parameters for H4 indirectly by quantifying H3 or the mixture of H3 and H4 would be unsuitable for evaluating the pharmacokinetics and pharmacodynamics relationship. This hypothesis was proven in a clinical study in which C max of H4 rather than H3 was correlated with platelet aggregation in humans after oral administration of clopidogrel (Kara zniewicz-Łada et al, 2014). More studies are required to investigate the role of the epimerization of thiolactone 2 and TMT in the variability in response to clopidogrel therapy.…”

P-Glycoprotein Polymorphism C3435T Is Associated with Dose-Adjusted Clopidogrel and 2-Oxo-Clopidogrel Concentration

“…Whether ABCB1 C3435T polymorphism influences the concentration of clopidogrel metabolites is still inconclusive. Some studies show the association only at the prodrug level [24] . Mega et al [25] suggested that it did not affect maximum plasma concentration of thiol clopidogrel metabolite achieved.…”

The pharmacokinetic interaction between levofloxacin and sunitinib

“…The reduction of the collected blood samples can be useful from the clinical and also economical point of view. Strategies using a limited number of samples are useful also in therapeutic monitoring of anticoagulant drugs [20] and immunosuppressants [21].…”