title: In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study.
abstract: Robenacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animals. Whole blood assays were used to characterize in the cat the pharmacodynamics of robenacoxib for inhibition of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in comparison with other NSAIDs. Based on in vitro IC(50) COX-1:IC(50) COX-2 ratios, robenacoxib was COX-2 selective (ratio = 32.2), diclofenac (ratio = 3.9) and meloxicam (ratio = 2.7) were only weakly COX-2 preferential, and ketoprofen (ratio = 0.049) was COX-1 selective. In an in vivo pharmacokinetic ex vivo pharmacodynamic study, after both p.o. (1-2 mg/kg) and subcutaneous (2 mg/kg) dosing, robenacoxib achieved peak blood concentrations rapidly (T(max)  = 1 h for both administration routes) and was cleared from blood relatively rapidly (mean residence time was 1.70 h after p.o. and 1.79 h after subcutaneous dosing). In ex vivo COX isoform inhibition assays, orally (1-2 mg/kg) or subcutaneously (2 mg/kg) administered robenacoxib significantly inhibited COX-2, with a relatively short duration of action in the central compartment, and had no effect on COX-1. Therefore robenacoxib was COX-2 selective and spared COX-1 in vivo. In contrast, meloxicam (0.3 mg/kg via subcutaneous injection) inhibited both COX-1 and COX-2 isoforms significantly for at least 24 h, indicating nonselectivity in vivo.
authors.affiliation: Novartis Centre de Recherche Santé Animale SA, St-Aubin, Switzerland. vincent.schmid@novartis.com
authors.forename: V B
authors.initials: VB
authors.lastname: Schmid
authors.forename: W
authors.initials: W
authors.lastname: Seewald
authors.forename: P
authors.initials: P
authors.lastname: Lees
authors.forename: J N
authors.initials: JN
authors.lastname: King
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D002415:Cats / Q000097:blood*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004333:Drug Administration Routes; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; D004159:Diphenylamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C551524:robenacoxib