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Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves
Author(s) -
Landoni Maria Fabiana,
Lees Peter
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070806
Subject(s) - chemistry , enantiomer , pharmacodynamics , pharmacokinetics , exudate , pharmacology , ketoprofen , volume of distribution , stereochemistry , chromatography , medicine , botany , biology
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 LTB 4 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 B 2 (TxB 2 ) synthesis, exudate prostaglandin E 2 (PGE 2 ) 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. EC 50 values for inhibition of serum TxB 2 , exudate PGE 2 and 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 EC 50 values for inhibition of TxB 2 and PGE 2 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 EC 50 at 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. © 1995 Wiley‐Liss, Inc.