Abstract

Pharmacologic inhibition of thromboxane (TX) synthase can result in redirection of prostaglandin (PG) endoperoxide metabolism, possibly affecting platelet, vascular and renal function. This study explores the in vitro, ex vivo and in vivo effects of dazoxiben, an orally active TX-synthase inhibitor, on platelet and renal TXB2 production and associated changes in PG-endoperoxide metabolism. Dazoxiben inhibits TXB2 production in clotting human whole blood with an IC50 of 0.3 micrograms/ml and causes parallel enhancement of PGE2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha production. Similar redirection of PG-endoperoxide metabolism is observed ex vivo, after the oral administration of 1.5 and 3.0 mg/kg to six healthy volunteers. Plasma 6-keto-PGF1 alpha ranges between less than 4 and 8 pg/ml during the first 3 h. Urinary TXB2 excretion, a reflection of renal TXA2 production, is significantly reduced by 30% with no evidence of redirection of renal PG-endoperoxide metabolism. In vitro inhibition of TXB2 production in rat kidney glomeruli requires significantly higher dazoxiben concentration (IC50 = 1.60 micrograms/ml) than in rat whole blood (IC50 = 0.32 micrograms/ml) and is not associated with changes in PGE2, PGF2 alpha and 6-keto-PGF1 alpha production. These results demonstrate quantitatively and qualitatively diverse effects of dazoxiben in different TXA2-producing cells and suggest the possibility of developing tissue-selective TX-synthase inhibitors.