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- Title
Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2.
- Authors
King, J. N.; Dawson, J.; Esser, R. E.; Fujimoto, R.; Kimble, E. F.; Maniara, W.; Marshall, P. J.; O'Byrne, L.; Quadros, E.; Toutain, P. L.; Lees, P.
- Abstract
This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t1/2 < 1 min), whilst COX-2 binding was slowly reversible ( t1/2 = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2–30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40–0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall–Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF1α concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.
- Subjects
CYCLOOXYGENASE 2 inhibitors; PHARMACOLOGY; EXUDATES &; transudates; EDEMA; ENDOTOXINS; BLOOD proteins; NONSTEROIDAL anti-inflammatory agents
- Publication
Journal of Veterinary Pharmacology & Therapeutics, 2009, Vol 32, Issue 1, p1
- ISSN
0140-7783
- Publication type
Article
- DOI
10.1111/j.1365-2885.2008.00962.x