10
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background and Objective

          Approximately 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.

          Methods

          The 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.

          Results

          The pharmacokinetic parameter values for the H3 and H4 isomers determined in the studied group of patients treated with clopidogrel 75 mg (maximum plasma concentration [ C max] 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 [AUC t ] 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 C max of the active H4 isomer and platelet aggregation ( p = 0.025).

          Conclusion

          The C max of the active H4 isomer and platelet aggregation measured by the Multiplate analyser may serve as markers of the patient response to clopidogrel therapy.

          Related collections

          Most cited references35

          • Record: found
          • Abstract: found
          • Article: not found

          Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.

          The addition of clopidogrel to aspirin treatment reduces ischemic events in a wide range of patients with cardiovascular disease. However, recurrent ischemic event occurrence during dual antiplatelet therapy, including stent thrombosis, remains a major concern. Platelet function measurements during clopidogrel treatment demonstrated a variable and overall modest level of P2Y(12) inhibition. High on-treatment platelet reactivity to adenosine diphosphate (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients. Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.

            The aim of the current study is to identify the human cytochrome P450 (P450) isoforms involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. In the in vitro experiments using cDNA-expressed human P450 isoforms, clopidogrel was metabolized to 2-oxo-clopidogrel, the immediate precursor of its pharmacologically active metabolite. CYP1A2, CYP2B6, and CYP2C19 catalyzed this reaction. In the same system using 2-oxo-clopidogrel as the substrate, detection of the active metabolite of clopidogrel required the addition of glutathione to the system. CYP2B6, CYP2C9, CYP2C19, and CYP3A4 contributed to the production of the active metabolite. Secondly, the contribution of each P450 involved in both oxidative steps was estimated by using enzyme kinetic parameters. The contribution of CYP1A2, CYP2B6, and CYP2C19 to the formation of 2-oxo-clopidogrel was 35.8, 19.4, and 44.9%, respectively. The contribution of CYP2B6, CYP2C9, CYP2C19, and CYP3A4 to the formation of the active metabolite was 32.9, 6.76, 20.6, and 39.8%, respectively. In the inhibition studies with antibodies and selective chemical inhibitors to P450s, the outcomes obtained by inhibition studies were consistent with the results of P450 contributions in each oxidative step. These studies showed that CYP2C19 contributed substantially to both oxidative steps required in the formation of clopidogrel active metabolite and that CYP3A4 contributed substantially to the second oxidative step. These results help explain the role of genetic polymorphism of CYP2C19 and also the effect of potent CYP3A inhibitors on the pharmacokinetics and pharmacodynamics of clopidogrel in humans and on clinical outcomes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.

              Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.
                Bookmark

                Author and article information

                Contributors
                +48-61-8546432 , +48-61-8546430 , mkaraz@ump.edu.pl
                Journal
                Clin Pharmacokinet
                Clin Pharmacokinet
                Clinical Pharmacokinetics
                Springer International Publishing (Cham )
                0312-5963
                1179-1926
                15 October 2013
                15 October 2013
                2014
                : 53
                : 155-164
                Affiliations
                [ ]Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznan, Poland
                [ ]Division of Cardiology–Intensive Therapy, Department of Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355 Poznan, Poland
                [ ]Department of General and Vascular Surgery, Poznan University of Medical Sciences, ½ Długa Street, 61-848 Poznan, Poland
                [ ]First Department of Cardiology, Poznan University of Medical Sciences, ½ Długa Street, 61-848 Poznan, Poland
                Article
                105
                10.1007/s40262-013-0105-2
                3899497
                24127209
                c3bf7328-c6d0-4be1-a54f-7d4b2cf079d1
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Categories
                Original Research Article
                Custom metadata
                © Springer International Publishing Switzerland 2014

                Comments

                Comment on this article