Inhibition of human platelet cyclo-oxygenase activity by sulfinpyrazone and three of its metabolites.
Sulfinpyrazone and three of its major metabolites were compared in vitro for their inhibitory effect on human platelet cyclo-oxygenase activity. Sulfinpyrazone appeared to be about 15-20 times less potent than its sulfide metabolite (G25671) and 6-7 times less potent than the other two compounds, the sulfone metabolite (G31442) and p-hydroxysulfide (G33378). All four compounds were apparently competitive inhibitors of platelet cyclo-oxygenase activity. Comparison of the potency of sulfinpyrazone and its metabolites, as determined in the present study and the plasma levels previously measured in man, indicates that sulfinpyrazone and G33378 were not potent enough to be effective in man. G31442 showed inhibitory potency slightly lower than its corresponding plasma levels, whereas G25671 was effective at concentrations well below those found in human plasma. This study supports the hypothesis that sulfinpyrazone metabolites (in particular the sulfide) rather than the drug itself affect platelet function when administered therapeutically.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology*; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008315:Malondialdehyde / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D013442:Sulfinpyrazone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; C042256:G 31442; C042258:G 33378; D016718:Arachidonic Acid; C042257:G 25671; D008315:Malondialdehyde; D013929:Thromboxane B2; D011451:Prostaglandin-Endoperoxide Synthases; D013442:Sulfinpyrazone