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Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function — a flow cytometry study

2003; Oxford University Press; Volume: 24; Issue: 19 Linguagem: Inglês

10.1016/s0195-668x(03)00442-1

1522-9645

H. Neubauer,

Platelet Disorders and Treatments

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.