The antiaggregating activity of clopidogrel is not affected by N-acetyl L-cysteine

N-acetyl L-cysteine (NAC) is widely used to treat obstructive bronchopulmonary diseases. It has thiol reactive properties, accounting for its mucolytic activity. Clopidogrel is a potent antithrombotic compound, metabolised by the liver which generates an active metabolite containing a thiol reactive group, responsible for an irreversible interaction with the platelet P2Y(12) ADP receptor. The aim of this study was to determine if NAC interferes with the antiaggregating activity of clopidogrel. For this purpose, NAC (100 micro M) was incubated with platelets from rats treated or not with clopidogrel (5 mg/kg, PO, -2 h). Clopidogrel treatment strongly inhibited aggregation but this effect was not modified by NAC. In another experiment, a low concentration of the active metabolite of clopidogrel (0.3 micro g/ml) was incubated with platelets from men or rats, in the absence or presence of NAC (100 micro M). When stimulated by ADP (2.5 micro M), platelet aggregation was inhibited by the active metabolite when incubated alone. In the presence of NAC, the inhibition by the active metabolite was not modified, therefore clearly indicating that NAC cannot reduce the thiol reactive part of the active metabolite of clopidogrel and does not interfere with its anti-aggregating activity. Moreover, in rats treated for 5 days with NAC (150 mg/kg), the activity of clopidogrel (5 or 10 mg/kg) against ADP-induced platelet aggregation was neither inhibited nor increased. This demonstrates that the generation of the active metabolite of clopidogrel is not affected by NAC. In conclusion, we have found that NAC does not restore the "normal" properties of P2Y(12) on platelets from clopidogrel-treated animals, it does not interfere with the antiaggregating activity of the active metabolite of clopidogrel, and does not interfere with the generation of the active metabolite.