Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib

Authors


  • Present address of J. M. Giraudel: Novartis Centre de Recherche Santé Animale SA, CH-1566 Saint-Aubin FR, Switzerland.

Prof. Peter Lees, Department of Veterinary Basic Sciences, Royal Veterinary College, Hawkshead Campus, North Mymms, Hatfield, Hertfordshire AL 9 7TA, UK. E-mail: plees@rvc.ac.uk

Abstract

Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration–time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B2 provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC50 were 28.9 (16.4–51.1) μm (COX-1) and 0.058 (0.010–0.340) μm (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC50/IC50), 451.6 (IC95/IC95) and 17.05 (IC20/IC80). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.

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