title: Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves.
abstract: The pharmacokinetics (PK) and pharmacodynamics (PD) of (S)- and (R)-ketoprofen (KTP) enantiomers were studied in calves after intravenous administration of each enantiomer at a dose of 1.5 mg/kg. Pharmacodynamic properties were evaluated using a model of acute inflammation, comprising subcutaneously implanted tissue cages stimulated by intracaveal injection of carrageenan. Chiral inversion of (R)-KTP to the (S)-antipode occurred. The R:S ratio in plasma was 33:1 5 min after administration, decreasing to 1:1 at 8 h. The calculated extent of inversion was 31 +/- 7%. The R:S ratio in inflammatory exudate was of the order 3:1 at all the sampling times and the ratio in transudate was approximately 2:1 for 6 h, declining to 1:1 at 30 h. Only (S)-KTP was detected in biological fluids after administration of this enantiomer. Elimination half-life was longer for the (S) (2.19 h) than the (R)-enantiomer (1.30 h) and volume of distribution was also somewhat higher for the (S)-enantiomer. Body clearance values were 0.119 l/kg/h for (S)-KTP and 0.151 l/kg/h for the (R)-antipode. For (R)-KTP effects obtained were considered as a hybrid, since they potentially reflect the actions of both enantiomers. Concentrations of LTB4 and the cytokines interleukin-1, interleukin-6, and tumor necrosis factor alpha, in exudate were not significantly affected by either (R)- or (S)-KTP treatments. Inhibition of ex vivo thromboxane B2 (TxB2) synthesis, exudate prostaglandin E2 (PGE2) synthesis, beta-glucuronidase release (beta-glu), and bradykinin-induced skin swelling was significant in both treated groups. PK/PD modelling was applied to the (S)-KTP treatment only. EC50 values for inhibition of serum TxB2, exudate PGE2 and beta-glu and BK-induced swelling were 0.047, 0.042, 0.101, and 0.038 microgram/ml, respectively. It is concluded that the low EC50 values for inhibition of TxB2 and PGE2 by (S)-KTP are likely to explain the effects produced by (R)-KTP administration, since concentrations of (S)-KTP in exudate of these calves following chiral inversion were at least 5 times higher than the EC50 at all sampling times. The data for beta-glu and bradykinin-induced swelling inhibition indicate possible inhibitory actions of (R)-KTP as well as (S)-KTP.
authors.affiliation: Department of Veterinary Basic Sciences, Royal Veterinary College, Hawkshead Campus, Hatfield, Herts, United Kingdom.
authors.forename: M F
authors.initials: MF
authors.lastname: Landoni
authors.forename: P
authors.initials: P
authors.lastname: Lees
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002417:Cattle / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015194:Diffusion Chambers, Culture; D015232:Dinoprostone / Q000097:blood; D005122:Exudates and Transudates / Q000378:metabolism; D006207:Half-Life; D007249:Inflammation / Q000378:metabolism; D007275:Injections, Intravenous / Q000662:veterinary; D015850:Interleukin-6 / Q000097:blood; D007660:Ketoprofen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D007660:Ketoprofen; D015232:Dinoprostone