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

Abstract

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 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM 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 ID(50) 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 ID(50) value of 0.24 mg kg(-1). 6. 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.

• Authors: Ronald Esser, Carol Berry, Zhengming Du, Janet Dawson, Alyson Fox, Roger A Fujimoto, William Haston, Earl F Kimble, Julie Koehler, Jane Peppard, Elizabeth Quadros, Joseph Quintavalla, Karen Toscano, Laszlo Urban, John van Duzer, Xiaoli Zhang, Siyuan Zhou, Paul J Marshall
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 144 Issue 4 Pg. 538-50 (Feb 2005) ISSN: 0007-1188 [Print] England
• PMID: 15655513 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Membrane Proteins
• Organic Chemicals
• Diclofenac
• Thromboxane B2
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone
• lumiracoxib

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacokinetics, pharmacology, therapeutic use)
• Arthritis, Experimental (drug therapy)
• Biological Availability
• Blood Platelets (drug effects, metabolism)
• Cell Line
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Diclofenac (analogs & derivatives)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Edema (drug therapy)
• Female
• Fever (drug therapy)
• Fibroblasts (drug effects, metabolism)
• Humans
• Hyperalgesia (drug therapy)
• Male
• Membrane Proteins
• Organic Chemicals (pharmacokinetics, pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley
• Rats, Wistar
• Skin (cytology)
• Thromboxane B2 (metabolism)