Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.
OBJECTIVE
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 < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (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.
Atherton
Clare
C
Division of Gastroenterology, University Hospital, Nottingham, United Kingdom.
Jones
John
J
McKaig
Brian
B
Bebb
James
J
Cunliffe
Rob
R
Burdsall
Jake
J
Brough
Joanne
J
Stevenson
Diane
D
Bonner
Johanne
J
Rordorf
Christiane
C
Scott
Graham
G
Branson
Janice
J
Hawkey
Christopher J
CJ
D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives; D004064:Digestive System / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D005773:Gastroscopy; D006801:Humans; D007408:Intestinal Absorption; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D009930:Organic Chemicals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D012449:Safety
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009930:Organic Chemicals; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C473384:lumiracoxib