Quantitation of drug levels and platelet receptor blockade caused by a thromboxane antagonist.
SQ 28,668 is a structural analog of thromboxane A2. It inhibits the effects of thromboxane in vitro. Fifty-six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg. Plasma drug concentrations increased in a dose-dependent manner. The shape of the plasma drug concentration-time curve was consistent with enterohepatic recirculation. The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2 with a platelet receptor dissociation constant (estimated by Schild analysis) of about 19 nmol/L. Approximately 94% occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time. Dose-ranging studies of antithrombotic drugs are difficult and expensive. For this reason, a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000293:Adolescent; D000328:Adult; D002849:Chromatography, Gas; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011897:Random Allocation; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology
D011450:Prostaglandin Endoperoxides, Synthetic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C050448:SQ 28668