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 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.
Esser
Ronald
R
Arthritis Bone Metabolism at Novartis Institute for Biomedical Research, East Hanover, NJ, USA.
Berry
Carol
C
Du
Zhengming
Z
Dawson
Janet
J
Fox
Alyson
A
Fujimoto
Roger A
RA
Haston
William
W
Kimble
Earl F
EF
Koehler
Julie
J
Peppard
Jane
J
Quadros
Elizabeth
E
Quintavalla
Joseph
J
Toscano
Karen
K
Urban
Laszlo
L
van Duzer
John
J
Zhang
Xiaoli
X
Zhou
Siyuan
S
Marshall
Paul J
PJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004008:Diclofenac / Q000031:analogs & derivatives; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000188:drug therapy; D005260:Female; D005334:Fever / Q000188:drug therapy; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D008565:Membrane Proteins; D009930:Organic Chemicals / Q000493:pharmacokinetics / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012867:Skin / Q000166:cytology; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009930:Organic Chemicals; D004008:Diclofenac; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C473384:lumiracoxib