Pharmacokinetics of CGS 12970 and inhibition of thromboxane synthesis after oral administration in healthy adults.
The pharmacokinetics and pharmacodynamics of biochemical effect of a selective thromboxane synthase inhibitor, CGS 12970, were studied in healthy male volunteers after a dosing scheme of either 200 mg once daily or 100 mg twice a day for 6 days. The peak plasma concentration appeared 1 to 2 hours after administration, followed by a biexponential decline with half life values of about 1 and 7 hours, respectively. The mean oral clearance was 16 L/hr. Biochemically, the capacity of the platelets to form thromboxane A2 ex vivo (serum) was inhibited greater than 90% at both doses. In contrast to the short plasma half-life, the suppression of ex vivo serum thromboxane production was maintained greater than 70% to 80% at 48 hours after dosing. Inhibition of the thromboxane production in vivo (urine) was also substantial, but incomplete at both doses (200 mg daily; thromboxane B2, 75%; 2,3-dinor-thromboxane B2, 83%; 11-dehydrothromboxane B2, 90%). The urinary excretion, however, returned to the predose level at the end of a 1-week follow-up period after the last dosing. In conclusion, CGS 12970 is an orally active, reversible inhibitor of thromboxane synthase with a prolonged duration of action in humans.
Martin
L L
LL
Department of Exploratory Clinical Pharmacology, Ciba-Geigy Corporation, Summit, NJ 07901.
Schaffer
A V
AV
Piraino
A
A
Linberg
L
L
Singh
K
K
Rakhit
A
A
Douglas
F L
FL
D000284:Administration, Oral; D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001798:Blood Proteins; D011725:Pyridines; D013928:Thromboxane A2; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D013930:Thromboxane-A Synthase