Prostacyclin biosynthesis, platelet function and drug metabolite formation during chronic sulfinpyrazone therapy. Circulation. 66 (Part II):323

metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thrombox-ane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were revers-ibly inhibited in a dose-dependent manner. Aggre-gation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0,uM) in platelet-rich plasma as well as both aggregation and nucleotide re-lease induced by collagen (95 Zg/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGFia (PGI-M). PGI-M excretion was increased b