The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760
Nichols, A.J.; Vasko, J.A.; Koster, P.F.; Valocik, R.E.; Rhodes, G.R.; Miller-Stein, C.; Boppana, V.; Samanen, J.M.
Journal of Pharmacology and Experimental Therapeutics 270(2): 614-621
1994
ISSN/ISBN: 0022-3565 PMID: 8071853 Document Number: 437188
The in vivo pharmacological profile of SK&F 106760 (N-alpha-acetylcyclo(S,S)-cysteinyl-N-alpha-methylarginyl-glycyl-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 vivo whole blood platelet aggregation induced by collagen (5 mu-g/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial a-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 +- 12 min, which accounted for 79 +- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +- 26 ml/kg and the plasma clearance was 3.4 +- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood 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, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action. Furthermore, at a dose of 3.0 mg/kg i.v., SK&F 106760 produced a 78% reduction in the incidence of fibrin/platelet-dependent coronary artery thrombosis. At 0.3 to 3.0 mg/kg i.v., SK&F 106760 produced a dose-related enhancement in the thrombolytic efficacy of streptokinase in anesthetized dogs, by reducing the time to reperfusion and inhibiting reocclusion. However, SK&F 106760 (100 mu-M) did not potentiate streptokinase-mediated canine clot lysis in vitro, indicating that SK&F 106760 has no direct effect on the intrinsic fibrinolytic activity of streptokinase. Thus, SK&F 106760 is a potent antithrombotic agent in vivo capable of inhibiting both platelet- and fibrin/platelet-dependent coronary artery thrombosis and enhancing the thrombolytic efficacy of streptokinase at doses that inhibit ex vivo platelet aggregation.