DIFFERENTIAL-EFFECTS OF DAZOXIBEN, A SELECTIVE THROMBOXANE SYNTHASE INHIBITOR, ON PLATELET AND RENAL PROSTAGLANDIN ENDOPEROXIDE METABOLISM

  • 1 January 1984
    • journal article
    • research article
    • Vol. 228  (2) , 472-477
Abstract
Pharmacologic inhibition of thromboxane (TX) synthase can result in redirection of prostaglandin (PG) endoperoxide metabolism, possibly affecting platelet, vascular and renal function. The in vitro, ex vivo and in vivo effects of dazoxiben, an orally active TX-synthase inhibitor was studied 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 [median inhibitory concentration] of 0.3 .mu.g/ml and causes parallel enhancement of PGE2 > PGF2.alpha. > 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 6 healthy volunteers. Plasma 6-keto-PGF1.alpha. ranges between < 4 and 8 pg/ml during the 1st 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 .mu.g/ml) than in rat whole blood (IC50 = 0.32 .mu.g/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 of developing tissue-selective TX-synthase inhibitors.