Pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor lumiracoxib in the lipopolysaccharide-stimulated rat air pouch model.
OBJECTIVE
To investigate the pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor, lumiracoxib, in the rat air pouch.


METHODS
Air pouches were injected with lipopolysaccharide to stimulate prostaglandin E2 (PGE2) production 1h after lumiracoxib treatment. Pouch fluid samples were collected 6 or 24 h after lumiracoxib administration to measure PGE2 levels. Lumiracoxib concentrations in pouch fluid and plasma were measured by mass spectrometry.


RESULTS
Oral administration of lumiracoxib resulted in dose-dependent inhibition of PGE2 production 6 and 24 h post-dose. The estimated ED50 values for inhibition of PGE2 production were 0.1 and 2.0 mg/kg at 6 and 24 h, respectively. Lumiracoxib concentrations in plasma and pouch fluid increased in proportion to dose. There was a strong positive correlation between lumiracoxib concentrations in plasma and pouch fluid compartments. Lumiracoxib concentrations were higher in plasma than in pouch fluid 6 h post-dose, but at 24 h post-dose, pouch fluid concentrations were > or =4-fold greater than plasma concentrations.


CONCLUSIONS
Lumiracoxib readily enters the air pouch and persists in this extravascular compartment for a longer period of time than in plasma. This distribution profile may contribute to the ability of lumiracoxib to inhibit PGE2 production up to 24 h after dosing.
Esser
Ronald E
RE
Arthritis and Bone Metabolism, Novartis Institutes for BioMedical Research, Novartis Pharmaceuticals Corp., One Health Plaza, East Hanover, NJ 07936, USA.
Miserendino-Molteni
Rocca
R
Sharr
Michele
M
Zhang
Xiaoli
X
Porter
Wilma
W
Ramos
Luis
L
Cramer
Jeffrey A
JA
Zhuang
Shumin
S
Georgieva
Anna
A
Maniara
Wieslawa
W
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009930:Organic Chemicals / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D009930:Organic Chemicals; D004008:Diclofenac; D015232:Dinoprostone; C473384:lumiracoxib