Clinical pharmacokinetics and pharmacodynamics of celecoxib - A selective cyclo-oxygenase-2 inhibitor

Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first spec ific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib als o has analgesic and anticancer properties. The selective inhibition of COX- 2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Uppe r gastrointestinal complication rates in clinical trials are significantly lower fur celecoxib than for traditional nonselective NSAIDs (e.g. naproxen , ibuprofen and diclofenac). The rate of absorption of celexocib is moderate when given orally (peak pla sma drug concentration occurs after 2 to 4 hours), although the extent of a bsorption is not known. Celexocib is extensively protein bound, primarily t o plasma albumin. and has an apparent volume of distribution of 455 +/- 166 L in humans. The area under the plasma concentration-time curve (AUC) of ce lecoxib increases in proportion to increasing oral doses between 100 and 80 0 mg. Celecoxib is eliminated following biotransformation to carboxylic aci d :Ind glucuronide metabolites that are excreted in urine and faeces. with little drug (2%) being eliminated unchanged in the urine. Celecoxib is meta bolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an eli mination half-life of about 11 hours in healthy individuals. Racial differe nces in drug disposition and pharmacokinetic changes in the elderly have be en reported for celecoxib. Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/ h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been reported that the steady-state AUC is increased by approximate ly 40% and 180% in patients with mild and moderate hepatic impairment, resp ectively. Celecoxib does not appear to interact with warfarin, ketoconazole or methot rexate; however. clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9. in creased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme.