Summary

N-acetyl L-cysteine (NAC) is widely used to treat obstructivebronchopulmonary diseases. It has thiol reactive properties,accounting for its mucolytic activity. Clopidogrel is a potentantithrombotic compound, metabolised by the liver which gen-eratesan active metabolite containing a thiol reactive group,responsible for an irreversible interaction with the plateletP2Y₁₂ ADP receptor.The aim of this study was to determine if NAC interferes withthe antiaggregating activity of clopidogrel. For this purpose,NAC (100 µM) was incubated with platelets from rats treatedor not with clopidogrel (5 mg/kg, PO, -2 h). Clopidogrel treat-mentstrongly inhibited aggregation but this effect was notmodified by NAC. In another experiment, a low concentrationof the active metabolite of clopidogrel (0.3 µg/ml) was incubat-edwith platelets from men or rats, in the absence or presenceof NAC (100 µM).When stimulated by ADP (2.5 µM), plateletaggregation was inhibited by the active metabolite when incu-batedalone. In the presence of NAC, the inhibition by theactive metabolite was not modified, therefore clearly indicatingthat NAC cannot reduce the thiol reactive part of the activemetabolite of clopidogrel and does not interfere with its anti-aggregatingactivity. Moreover, in rats treated for 5 days withNAC (150 mg/kg), the activity of clopidogrel (5 or 10 mg/kg)against ADP-induced platelet aggregation was neither inhibitednor increased. This demonstrates that the generation of theactive metabolite of clopidogrel is not affected by NAC.In conclusion, we have found that NAC does not restore the“normal” properties of P2Y₁₂ on platelets from clopidogrel-treatedanimals, it does not interfere with the antiaggregatingactivity of the active metabolite of clopidogrel, and does notinterfere with the generation of the active metabolite.