Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). 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-PGF(1α) (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.

Conflict of interest statement

CONFLICT OF INTEREST

The regulatory sponsor of this clinical study was CrystalGenomics, Inc., Seoul, Korea. William K. Schmidt, who served as the study director, is the US representative for CrystalGenomics, Inc., Emeryville, CA. G.A.F. has consulted for Lilly, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo on NSAIDs or NSAID-related drugs in the past year. The other authors declared no conflict of interest.

Figures

Figure 1

CONSORT flow diagram. *Randomization error, that is, period II treatment assignments, were unlinked to period I treatments, thus not achieving the planned crossover group sizes of n = 6.

Figure 2

CG100659 drug concentrations in plasma and whole blood (left) after single oral administrations of CG100659 (2 mg) and (8 mg). Both dose levels demonstrate the marked partition of CG100649 into erythrocytes. Celecoxib plasma concentrations after single oral administration of 200 mg show comparable drug exposure profiles for periods I and II (right). Note that the ordinate for CG100649 drug concentrations as well as both abscissas are log-scaled to capture the wide range.

Figure 3

Urinary PGI-M concentrations over time expressed as percentage change from baseline. The horizontal reference line indicates the percentage change from zero. Box plots indicate mean (dot), median (center line of the box), first and third interquartile ranges (lower and upper lines), and minimum and maximum values (lower and upper whiskers). PGI, metabolite of prostacyclin.

Figure 4

Serum TxB2 concentrations over time expressed as percentage change from baseline. The reference line indicates the percentage change from zero. TxB2, serum thromboxane. Skarke et al. Page 13 Clin Pharmacol