Ketoprofen in the cat: pharmacodynamics and chiral pharmacokinetics.
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) microg h/mL after IV and 6.36 (S(+)KTP) and 1.83 (R(-)KTP) microg h/mL after oral dosing. Bioavailability after oral dosing was virtually complete. Reduction in ex vivo serum thromboxane (TX)B(2) 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 1mg/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.
Lees
P
P
Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawkshead Campus, North Mymms, Hatfield, Herts. AL9 7TA, UK. plees@rvc.ac.uk
Taylor
P M
PM
Landoni
F M
FM
Arifah
A K
AK
Waters
C
C
D000284:Administration, Oral; D000818:Animals; D002351:Carrageenan; D002415:Cats; D018592:Cross-Over Studies; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D007275:Injections, Intravenous; D007660:Ketoprofen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D012881:Skin Temperature / Q000187:drug effects; D013045:Species Specificity; D013237:Stereoisomerism
D002351:Carrageenan; D007660:Ketoprofen