A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B2 (TXB2) synthesis and short-lived inhibition of exudate prostaglandin E2 (PGE2) and TXB2 synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen displayed enantioselective pharmacokinetics, plasma concentrations of the R(-) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69:31 at 5 min to 96:4 at 3 h and plasma mean AUC values were 7524 and 1639 ng x h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t(1/2beta)) and mean residence time were greater for R(-) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(-) and S(+) vedaprofen maximum concentration (Cmax) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng x h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.