Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase.

Abstract

Clopidogrel, like the homologous thienopyridine derivative tidopidine, selectively inhibits platelet aggregation induced by ADP. We have previously described two nucleotide-binding sites on platelets related to ADPmediated platelet responses. The first is a high-affinity binding she for 2-methylthio-ADP (2-MeSADP) that is linked to the inhibition of stimulated adenylate cyclase. The second is the 100-kd exofacial membrane protein aggregin, which is labeled by the reactive ADP analogue 5'-p-fluorosulfonyibenzoyl adenosine (FSBA) that is related to shape change and aggregation. We set out to determine if either of these sites is blocked in vivo by clopidogrel or its active metabolite. Six subjects were given clopidogrel (75 mg/day for 10 days) in a double-blind crossover experiment All of the subjects developed prolonged bleeding times while taking the drug. The rate of onset of the effect on bleeding time varied among subjects. Platelet aggregation induced by ADP or thrombin was significantly impaired by the drug treatment, but no effect was detected on shape change. The incorporation of [ 3 H]FSBA into aggregin was also unaffected. Inhibition of adenylate cyclase by ADP or by 2-MeSADP was greatly reduced in all subjects, and in the case of 2-MeSADP, there was evidence for a noncompetitive effect Inhibition of adenylate cyclase by epinephrine was unaffected. In the three subjects for whom binding measurements were made, the number of binding sites for [32 P]2-MeSADP was reduced from 534±44 molecules per platelet during control and placebo periods (11 determinations) to 199±78 molecules per platelet during drug treatment (three determinations). There was no consistent change in the binding affinity. The inhibition of platelet function by clopidogrel is associated with a selective reduction in the number of functional receptors mediating the inhibition of stimulated adenylate cyclase activity by ADP.

Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis With Antithrombotic Enhancement by Aspirin in Nonhuman Primates

“…10,11,17,33,34 The present study underscores the selectivity of clopidogrel for abolishing ADP-mediated platelet activation and its lack of significant inhibitory effects on TRAP-induced platelet activation ( Table 1). The inhibition of collagen-induced platelet aggregation by clopidogrel is explained by the contribution made by ADP secretion from platelets activated by collagen ( Table 1).…”

“…22 Clopidogrel acts by irreversibly inactivating platelet ADP receptor-initiated signaling in a dose-dependent manner. 10,20,21 In a recently reported large-scale, randomized, controlled clinical trial, clopidogrel was shown to be significantly more effective than and at least as safe as aspirin in decreasing arterial thromboocclusive episodes in patients with symptomatic atherosclerotic disease. 22 Clinical trials reporting that ticlopidine plus aspirin markedly reduces thrombotic occlusion of coronary stents suggest that adding aspirin to clopidogrel therapy may enhance its antithrombotic efficacy.…”

P2 receptors and platelet function

“…The thienopyridine compounds are prodrugs which have to be metabolized by the liver in order to generate active metabolites. The active metabolite of clopidogrel [107] covalently binds cysteine residues of the P2Y 12 receptor, thus precluding the binding of ADP [108][109][110]. Moreover, it has been recently reported that clopidogrel's active metabolite disrupts homopolymers of the P2Y 12 receptor expressed in lipid rafts and partitions them out of lipid rafts [111], pointing to the importance of oligomerization and membrane localization on the function of this receptor.…”

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

“…Although CYP2C19 is not primarily involved in the metabolism of APs, it is an important enzyme involved in the metabolism of antidepressants and the antiplatelet drug, clopidogrel (16,25,26). Given that it is included in various commercially available genetic test kits, its genetic architecture is briefly discussed.…”