Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.

Abstract Background & Aims: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. Methods: Twenty four healthy subjects (aged 18–45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B 2 (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E 2 (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour 51 Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE 2 synthesis at the end of each treatment period by enzyme immunoassay. Results: Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B 2 vs. placebo). Gastric PGE 2 was reduced by 69% by naproxen ( P P 51 Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib. Conclusions: Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.