Cyclooxygenase inhibition, platelet function, and metabolite formation during chronic sulfinpyrazone dosing

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Abstract
The inhibitory effects of sulfinpyrazone are more marked ex vivo than in vitro, suggesting biotransformation to potentially active metabolites such as the sulfide and sulfone metabolites. As a platelet inhibitor, the sulfide metabolite is 10 times as potent as the parent and because of its long t1/2 [half-life], the former may lead to cumulative inhibition of platelet function in vivo during chronic sulfinpyrazone dosing. In this study, healthy subjects received sulfinpyrazone, 200 mg 4 times a day, for 6 days. Plasma levels of the sulfide metabolite rose slightly from 2.1 .+-. 0.8 .mu.g/ml 12 h after the 4th dose to 2.8 .+-. 0.8 .mu.g/ml 12 h after the 24th dose. This was associated with increasing inhibition of ex vivo platelet aggregation induced by platelet-activating factor during the dosing period, but inhibition of arachidonic acid-induced aggregation did not increase cumulatively during dosing and collagen-induced aggregation was not inhibited. Inhibition of platelet aggregation was no longer evident 24 h after the final dose of sulfinpyrazone. The effects of sulfinpyrazone on cyclooxygenase activity were assessed by measurement of thromboxane B2 production by thrombin-stimulated platelets ex vivo and urinary excretion of the major prostacyclin [prostaglandin[PG]I2] metabolite 2,3-dinor-6-keto-PGF1.alpha.. During sulfinpyranone dosing, thromboxane formation and prostacyclin biosynthesis were correspondingly lowered 50%-60%. The extent of this depression was of the same order on days 2 and 5 of dosing. After sulfinpyrazone, excretion of 2,3-dinor-6-keto-PGF1.alpha. recovered rapidly to levels before dosing, in contrast to the prolonged depression after chronic aspirin dosing. The weak potency and poor biochemical selectivity of sulfinpyrazone may have contributed to equivocal benefits in trials of its antithrombotic efficacy in vivo.