CLOPIDOGREL - A REVIEW OF ITS MECHANISM OF ACTION

The search for active antiplatelet drugs within the original chemical class of the thienopyridines, led to the discovery of clopidogrel, a n ovel ADP-selective agent whose antiaggregating properties are several times higher than those of ticlopidine, The antiaggregating properties of this compound are well known and, very recently, new results have clarified its mechanism of action. Clopidogrel is active only after in travenous or oral administration, and no circulating activity has been found in the plasma of treated animals or human volunteers. Experimen ts in rats have demonstrated that the antiaggregating activity was cau sed by a shortlasting metabolite generated in the liver by a cytochrom e P450-dependent pathway. The antiaggregating property of clopidogrel is caused by an inhibition of the binding of ADP to its platelet recep tors, and more specifically to the low affinity receptors, the high af finity binding sites being unaffected by clopidogrel, Several events i n the ADP activation process, including adenylyl cyclase down-regulati on, protein tyrosine phosphorylation, activation of the GPIIb-IIIa com plex, fibrinogen binding, aggregation and release, were inhibited by c lopidogrel and indicate their close relationship with the activation o f a low affinity receptor by ADP, In contrast, binding of ADP to its h igh affinity binding sites (clopidogrel-resistant receptors) induced s hape change, cytosolic calcium increase and phosphorylations of severa l other proteins, some events which were clopidogrel-sensitive. Thus, clopidogrel not only constitutes a potent antithrombotic drug in human s but also a good tool to study the effect of ADP on platelets.