Title: Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction
Abstract: The combination of clopidogrel with aspirin has demonstrated its effectiveness in reducing recurrent ischemic events and absolute mortality in patients with acute coronary syndromes and after stent implantation [ 1 Sabatine M.S. Cannon C.P. Gibson C.M. López-Sendón J.L. Montalescot G. Theroux P. et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005; 294: 1224-1232 Crossref PubMed Scopus (652) Google Scholar , 2 Steinhubl S.R. Berger P.B. Mann 3rd, J.T. Fry E.T. DeLago A. Wilmer C. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288: 2411-2420 Crossref PubMed Scopus (3008) Google Scholar , 3 Mehta S.R. Yusuf S. Peters R.J. Bertrand M.E. Lewis B.S. Natarajan M.K. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001; 358: 527-533 Abstract Full Text Full Text PDF PubMed Scopus (3015) Google Scholar , 4 Chen Z.M. Jiang L.X. Chen Y.P. Xie J.X. Pan H.C. Peto R. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366: 1607-1621 Abstract Full Text Full Text PDF PubMed Scopus (1698) Google Scholar ]. Clopidogrel is a prodrug that after oral ingestion is absorbed in the intestine. About 85% of the drug is hydrolyzed by esterases to an inactive carboxylic acid derivative. A small fraction is converted by hepatic cytochrome P450 (CYP3A4) monooxygenase to the active thiol metabolite that irreversibly binds to the adenosine diphosphate (ADP) P2Y12 receptor resulting in a partial inhibition of platelet aggregation. However, a considerable interindividual variability in platelet response to clopidogrel has been reported [ 5 Gurbel P.A. Bliden K.P. Hayes K.M. Yoho J.A. Herzog W.R. Tantry U.S. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol. 2005; 45: 1392-1396 Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar , 6 Gurbel P.A. Bliden K.P. Hiatt B.L. O'Connor C.M. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107: 2908-2913 Crossref PubMed Scopus (1435) Google Scholar , 7 Angiolillo D.J. Fernández-Ortiz A. Bernardo E. Ramírez C. Sabaté M. Bañuelos C. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J. 2004; 25: 1903-1910 Crossref PubMed Scopus (275) Google Scholar , 8 Serebruany V.L. Steinhubl S.R. Berger P.B. Malinin A.I. Bhatt D.L. Topol E.J. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005; 45: 246-251 Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar ]. Several mechanisms are associated with this phenomenon but definite evidence of the impact of each contributing factor is still lacking [ [9] van Werkum J.W. Heestermans A.A.C.M. Deneer V.H.M. Hackeng C.M. Ten Berg J.M. Clopidogrel resistance: Fact and Fiction. Futur Cardiol. 2006; 2: 215-228 Crossref PubMed Scopus (19) Google Scholar ]. Recently, Taubert and colleagues found a strong association between the peak plasma concentration of unchanged clopidogrel (and the active metabolite) with the degree of inhibition of platelet aggregation, suggesting that interindividual variability of intestinal absorption may be an important determinant of response variability to clopidogrel [ 10 Taubert D. Kastrati A. Harlfinger S. Gorchakova O. Lazar A. von Beckerath N. et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost. 2004; 92: 311-316 PubMed Google Scholar , 11 von Beckerath N. Taubert D. Pogatsa-Murray G. Schömig E. Kastrati A. Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005; 112: 2946-2950 PubMed Google Scholar ]. However, in ST-elevated myocardial infarction (STEMI) patients, few data exists about the onset of action and magnitude of platelet inhibition after a 600 mg loading dose of clopidogrel. Theoretically, it is possible that the physiological state of STEMI influences the intestinal absorption of clopidogrel. In order to investigate this hypothesis, we designed the present pilot study. Plasma concentrations of clopidogrel and its metabolites were serially measured after administration of a 600 mg loading dose of clopidogrel in STEMI patients and compared with the plasma concentrations of clopidogrel and its metabolites in healthy controls [ [10] Taubert D. Kastrati A. Harlfinger S. Gorchakova O. Lazar A. von Beckerath N. et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost. 2004; 92: 311-316 PubMed Google Scholar ].
Publication Year: 2008
Publication Date: 2008-01-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 167
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