Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves

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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 33:15 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 1/kg/h for (S)‐KTP and 0.151 1/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 LTB4and 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, β‐glucuronidase release (β‐glu), and bradykinin‐induced skin swelling was significant in both treated groups. PK/PD modelling was applied to the (S)‐KTP treatment only. EC50values for inhibition of serum TxB2, exudate PGE2and β‐glu and BK‐induced swelling were 0.047, 0.042, 0.101, and 0.038 μg/ml, respectively. It is concluded that the low EC50values for inhibition of TxB2and PGE2by (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 EC50at all sampling times. The data for β‐glu and bradykinin‐induced swelling inhibition indicate possible inhibitory actions of (R)‐KTP as well as (S)‐KTP.