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

Authors


Peter Lees Royal Veterinary College, University of London, Hawkshead Campus, North Mymms, Hatfield, Herts., AL9 7TA, UK.

Abstract

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 dis-played 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.h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t½β) and mean residence time were greater for R(–) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(–) and S(+) veda-profen maximum concentration (Cmax) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng.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.

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