Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2

1 This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2 Lumiracoxib inhibited purified COX-1 and COX-2 with K-i values of 3 and 0.06 muM, respectively. In cellular assays, lumiracoxib had an IC50 of 0.14 muM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 mM (HEK293 cells transfected with human COX-1). 3 In a human whole blood assay, IC50 values for lumiracoxib were 0.13 muM for COX-2 and 67 muM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4 Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5 Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B-2 (TxB(2)) generation with an ID50 of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E-2 (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID50 value of 0.24 mg kg(-1). Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7 Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.