THE IN-VIVO PHARMACOLOGICAL PROFILE OF THE NOVEL GLYCOPROTEIN-IIB IIIA ANTAGONIST, SK-AND-F-106760/

The in vivo pharmacological profile of SK&F 106760 methylarginyl-glycl -aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vi vo whole blood platelet aggregation induced by collagen (5 mu g/ml) wi th complete inhibition being produced for 5, 90 and 165 min after admi nistration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography af ter i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T-1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T-1/2 of 66 +/- 72 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time cu rve. The apparent steady-state volume of distribution was 259 +/- 26 m l/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma co ncentration of SK&F 106760 at which collagen-induced ex vivo whole blo od aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, S K&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of plat elet-dependent coronary artery thrombosis, with a dose-related duratio n of action. Furthermore, at a dose of 3.0 mg/kg i.v., SK&F 106760 pro duced a 78% reduction in the incidence of fibrin/platelet-dependent co ronary artery thrombosis. At 0.3 to 3.0 mg/kg i.v., SK&F 106760 produc ed a dose-related enhancement in the thrombolytic efficacy of streptok inase in anesthetized dogs, by reducing the time to reperfusion and in hibiting reocclusion. However, SK&F 106760 (100 mu M) did not potentia te streptokinase-mediated canine clot lysis in vitro, indicating that SK&F 106760 has no direct effect on the intrinsic fibrinolytic activit y of streptokinase. Thus, SK&F 106760 is a potent antithrombotic agent in vivo capable of inhibiting both platelet- and fibrin/platelet-depe ndent coronary artery thrombosis and enhancing the thrombolytic effica cy of streptokinase at doses that inhibit ex vivo platelet aggregation .