Comparative Impact on Prostanoid Biosynthesis of Celecoxib and the Novel Nonsteroidal Anti-Inflammatory Drug CG100649

Nonsteroidal anti‐inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase‐2 (COX‐2)‐dependent biosynthesis of prostacyclin (PGI2). CG100649 is a novel NSAID proposed to inhibit both COX‐2 and carbonic anhydrase (CA)‐I/‐II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX‐2. In a controlled, double‐blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3‐dinor‐6‐keto‐PGF1α (PGI‐M); the effect of CG100649 was dose‐dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX‐1‐dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX‐2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined. Clinical Pharmacology & Therapeutics (2012); 91 6, 986–993. doi:10.1038/clpt.2012.3