Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2

作者：Brendan F. McAdam, Francesca Catella-Lawson, Issam A. Mardini, Shiv C. Kapoor, John A. Lawson, Garret A. FitzGerald · 发表于：Proceedings of the National Academy of Sciences · 年份：1999 · DOI：10.1073/pnas.96.1.272 · 被引用次数：1313 · 研究领域：Inflammatory mediators and NSAID effects、Estrogen and related hormone effects、Eicosanoids and Hypertension Pharmacology

Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i)...