Copyright © 2003 by the European Society of Cardiology.
Clinical research
Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function — a flow cytometry study
Clinic of Cardiology and Angiology, Ruhr-University, Bochum, Germany
* Correspondence to: Dr A. Mügge, Clinic of Cardiology and Angiology, BG Kliniken Bergmannsheil/St Josef-Hospital, Ruhr-University, Gudrunstrasse 56, 44791 Bochum, Germany. Tel: +49 234 509 2301; Fax: +49 234 509 2303
E-mail address: andreas.muegge{at}ruhr-uni-bochum.de
Received 29 January 2003; revised 20 July 2003; accepted 28 July 2003
Abstract
Aims Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5'-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins.
Methods In patients with coronary artery disease (n=47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48h after oral administration of clopidogrel (loading dose 300mg, followed by 75mg daily). ADP-stimulated (1, 10, 100µmol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel.
Results Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10µmol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect.
Conclusion Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished—but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.
Key Words: Clopidogrel • platelets • statins • cytochrome P450 • P-selectin
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