Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study.
OBJECTIVE
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 48 h after oral administration of clopidogrel (loading dose 300 mg, followed by 75 mg daily). ADP-stimulated (1, 10, 100 micromol/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 (10 micromol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48 h 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.


CONCLUSIONS
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.
Neubauer
Horst
H
Clinic of Cardiology and Angiology, Ruhr-University, Bochum, Germany.
Günesdogan
Bülent
B
Hanefeld
Christoph
C
Spiecker
Martin
M
Mügge
Andreas
A
D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003327:Coronary Disease / Q000628:therapy*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011446:Prospective Studies; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine