Pharmacokinetics and pharmacodynamics of SM-20302, a GPIIb/IIIa receptor antagonist, in anesthetized dogs.
We examined the pharmacokinetic and pharmacodynamic properties of SM-20302, a GPIIb/IIIa receptor antagonist, in anesthetized dogs. SM-20302 was administered intravenously in doses of 30 (n=2), 100 (n=4), 300 (n=4), and 1,000 microg/kg (n=4). The half-life of the initial phase was 4 min, and that of the terminal phase was 162-209 min. SM-20302 produced a dose-dependent increase in the initial plasma concentration and the area under concentration-time curve but did not alter the volume of distribution, mean residence time, or plasma clearance. Plasma clearance for SM-20302 ranged from 6.58 to 9.73 ml/min/kg. All doses of SM-20302 inhibited (> or =90%) the ex vivo platelet 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 Emax model, the in vivo median inhibitory concentration (IC50) for SM-20302 was estimated to be 14-19 ng/ml in cPRP and 79-89 ng/ml in hPRP. To validate the calculated parameters, an infusion regimen was designed for the prevention of coronary artery thrombosis. Infusion of SM-20302 produced 64-67% inhibition of platelets in hPRP and maintained 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 with its in vivo antithrombotic efficacy.
Rebello
S S
SS
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Huang
J
J
Shiu
W J
WJ
Saito
K
K
Kaneko
M
M
Saitoh
Y
Y
Lucchesi
B R
BR
D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*
D001555:Benzene Derivatives; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C112851:SM 20302