Ketoprofen in the Cat: Pharmacodynamics and Chiral Pharmacokinetics
Lees, Peter and Taylor, Polly Monroe and Landoni, Maria Fabiana and Abdul Kadir, Arifah and Waters, C. (2003) Ketoprofen in the Cat: Pharmacodynamics and Chiral Pharmacokinetics. The Veterinary Journal, 165 (1). pp. 21-35. ISSN 1090-0233
Official URL: http://dx.doi.org/10.1016/S1090-0233(02)00168-5
The non-steroidal anti-inflammatory drug ketoprofen (KTP) was administered as the racemate to cats intravenously (IV) and orally at clinically recommended dose rates of 2 and 1 mg/kg, respectively, to establish its chiral pharmacokinetic and pharmacodynamic properties. After IV dosing, clearance was more than five times greater and elimination half-life and mean residence time were approximately three times shorter for R(−) KTP than for S(+) KTP. Absorption of both S(+) and R(−) enantiomers was rapid after oral dosing and enantioselective pharmacokinetics was demonstrated by the predominance of S(+) KTP, as indicated by plasma AUC of 20.25 (S(+)KTP) and 4.09 (R(−)KTP) μg h/mL after IV and 6.36 (S(+)KTP) and 1.83 (R(−)KTP) μg h/mL after oral dosing. Bioavailability after oral dosing was virtually complete. Reduction in ex vivo serum thromboxane (TX)B2 concentrations indicated marked inhibition of platelet cyclo-oxygenase (COX)-1 for 24 h after both oral and IV dosing and inhibition was statistically significant for 72 h after IV dosing. Both oral and IV rac-KTP failed to affect wheal volume produced by intradermal injection of the mild irritant carrageenan but wheal skin temperature was significantly inhibited by IV rac-KTP at some recording times. Possible reasons for the disparity between marked COX-1 inhibition and the limited effect on the cardinal signs of inflammation are considered. In a second experiment, the separate enantiomers of KTP were administered IV, each at the dose rate of 1 mg/kg. S(+)KTP again predominated in plasma and there was unidirectional chiral inversion of R(−) to S(+)KTP. Administration of both enantiomers again produced marked and prolonged inhibition of platelet COX-1 and, in the case of R(−)KTP, this was probably attributable to S(+)KTP formed by chiral inversion.
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