PHARMACOKINETICS AND PHARMACODYNAMICS OF SM-20302, A GPIIB IIIA RECEPTOR ANTAGONIST, IN ANESTHETIZED DOGS/

We examined the pharmacokinetic and pharmacodynamic properties of SM-2 0302, a GPIIb/IIIa receptor antagonist, in anesthetized dogs. SM-20302 was administered intravenously in doses of 30 (n = 2), 100 (n = 4), 3 00 (n = 4), and 1,000 mu g/kg (n = 4). The half-life of the initial ph ase was 4 min, and that of the terminal phase was 162-209 min. SM-2030 2 produced a dose-dependent increase in the initial plasma concentrati on and the area under concentration-time curve but did not alter the v olume of distribution, mean residence time, or plasma clearance. Plasm a clearance for SM-20302 ranged from 6.58 to 9.73 ml/min/kg. All doses of SM-20302 inhibited (greater than or equal to 90%) the ex vivo plat elet aggregation induced by adenosine diphosphate (ADP) or arachidonic acid (AA) in citrated platelet-rich plasma (cPRP). In heparinized PRP (hPRP), a dose-dependent (44-89%) inhibition was observed. By using a sigmoid E-max model, the in vivo median inhibitory concentration (IC5 0) for SM-20302 was estimated to be 14-19 ng/ml in cPRP and 79-89 ng/m l in hPRP. To validate the calculated parameters, an infusion regimen was designed for the prevention of coronary artery thrombosis. Infusio n of SM-20302 produced 64-67% inhibition of platelets in hPRP and main tained vessel patency despite vessel wall injury. The results suggest that SM-20302 exhibits linear pharmacokinetics and that its ability to inhibit platelet aggregation in hPRP may correlate more accurately wi th its in vivo antithrombotic efficacy.