title: A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation.
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 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.
authors.affiliation: Royal Veterinary College, University of London, Hatfield, Herts, UK.
authors.forename: P
authors.initials: P
authors.lastname: Lees
authors.forename: S A
authors.initials: SA
authors.lastname: May
authors.forename: M
authors.initials: M
authors.lastname: Hoeijmakers
authors.forename: A
authors.initials: A
authors.lastname: Coert
authors.forename: P V
authors.initials: PV
authors.lastname: Rens
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000097:blood; D005122:Exudates and Transudates / Q000378:metabolism; D005260:Female; D006736:Horses / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007275:Injections, Intravenous; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010976:Platelet Count; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D009281:Naphthalenes; D011422:Propionates; D013929:Thromboxane B2; D015232:Dinoprostone; C121784:2-(4-cyclohexyl-1-naphthalenyl)propanoic acid