W1, a novel oral antiplatelet agent with less resistance than clopidogrel

ABSTRACTClopidogrel is a clinical antiplatelet agent, about which there are major concerns because its antiplatelet efficiency decreases with insufficient metabolic activation, leading to “clopidogrel resistance.” We aimed to determine the antiplatelet effects of W1, a novel molecule composed of 2-O-clopidogrel and aspirin (1:1 ratio), on platelet aggregation ex vivo and thrombus formation in vivo, and its susceptibility to “clopidogrel resistance” in combination with other therapies in rats. Platelets were prepared, and an arteriovenous shunt thrombosis model was established using Wistar rats to measure platelet aggregation and thrombus formation, respectively. W1 markedly inhibited adenosine 5′-diphosphate (ADP)-induced platelet aggregation and thrombus formation dose-dependently (0.3, 1, and 3 mg/kg). W1 (3 mg/kg) acted rapidly at 0.5 h and lasted for 72 h. W1 prolonged bleeding and clotting times (BT and CT, respectively) in mice, confirming its antithrombotic properties. Compared with clopidogrel 10 mg/kg, the positive control, W1 3 mg/kg exerted equivalent effects on the above specifications. Additionally, cyclic adenosine monophosphate (cAMP) levels, measured in rat platelets, increased rapidly after prostaglandin E1(PGE1, alprostadil) stimulation of the vehicle control (0.5% methyl cellulose suspension) and W1 (3 mg/kg)-treated groups. ADP (50 µm) reduced the control levels more remarkably than W1 did (p < 0.05 in 3 min or p < 0.001 at 5 min), suggesting that W1 suppressed ADP-induced cAMP reduction. This was associated with a significant platelet reactivity inhibition measured using the vasodilator-stimulated phosphoprotein (VASP) assay. Clopidogrel or W1 co-administration with or without omeprazole and amlodipine to rats to investigate the pharmacodynamic interactions revealed that W1 exhibited more stable and potent antithrombotic effects than clopidogrel did. In conclusion, both W1 and clopidogrel showed antiplatelet and antithrombotic effects, while the former exhibited less “clopidogrel resistance” in combination with omeprazole or amlodipine, two drugs that inhibit clopidogrel metabolism. Therefore, this study implies that W1 may be a promising oral antiplatelet agent for reducing “clopidogrel resistance” after percutaneous coronary intervention (PCI).