title: Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2.
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 t(1/2) << 1 min), whilst COX-2 binding was slowly reversible (t(1/2) = 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 PGF(1alpha) 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.
authors.affiliation: Novartis Animal Health Inc., CH-4058, Basel, Switzerland. jonathan.king@novartis.com
authors.forename: J N
authors.initials: JN
authors.lastname: King
authors.forename: J
authors.initials: J
authors.lastname: Dawson
authors.forename: R E
authors.initials: RE
authors.lastname: Esser
authors.forename: R
authors.initials: R
authors.lastname: Fujimoto
authors.forename: E F
authors.initials: EF
authors.lastname: Kimble
authors.forename: W
authors.initials: W
authors.lastname: Maniara
authors.forename: P J
authors.initials: PJ
authors.lastname: Marshall
authors.forename: L
authors.initials: L
authors.lastname: O'Byrne
authors.forename: E
authors.initials: E
authors.lastname: Quadros
authors.forename: P L
authors.initials: PL
authors.lastname: Toutain
authors.forename: P
authors.initials: P
authors.lastname: Lees
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004159:Diphenylamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005334:Fever / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D007527:Isoenzymes; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000473:pathology; D010648:Phenylacetates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010648:Phenylacetates; D004159:Diphenylamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C551524:robenacoxib