Ketoprofen in the Cat: Pharmacodynamics and Chiral Pharmacokinetics

University of Cambridge, Cambridge, England, United Kingdom
The Veterinary Journal (Impact Factor: 1.76). 02/2003; 165(1):21-35. DOI: 10.1016/S1090-0233(02)00168-5
Source: PubMed


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.

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Available from: Fabiana Landoni, Jun 04, 2014
    • "The model did not include the R(À) enantiomer, as it was considered to be devoid of activity on cyclooxygenase at the concentrations achieved. Indeed, S(+) ketoprofen is the eutomer of the S(+)/R(À) ketoprofen enantiomeric pair (Lees et al., 2003). The response is indirect because it is the consequence of a dynamic physiologic equilibrium between PGE 2 production after carrageenan injection , the natural clearance of PGE 2 from exudate and the reversible inhibition of COX-2 by NSAIDs, preventing the build-up of PGE 2 in exudate as in equation 3 (Dayneka et al., 1993 "
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    ABSTRACT: Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three-period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half-life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half-life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC50COX-1/IC50COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood.
    Journal of Veterinary Pharmacology and Therapeutics 03/2014; 37(4). DOI:10.1111/jvp.12107 · 1.19 Impact Factor
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    • "In humans, rats and mice [18-21], the absorption of ketoprofen is not stereoselective, but low enantioselectivity has been found in first-pass metabolism in humans [22]. However, in rats and cats, enantioselective pharmacokinetics were influenced by the oral route of administration compared to intravenous administration [21,23], whereas in elephants there were no significant differences [24]. In our previous study a second peak in total ketoprofen concentrations in plasma was observed in pigs [5], which may indicate enterohepatic circulation of the drug. "
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    ABSTRACT: Background Ketoprofen is a non-steroidal anti-inflammatory drug which has been widely used for domestic animals. Orally administered racemic ketoprofen has been reported to be absorbed well in pigs, and bioavailability was almost complete. The objectives of this study were to analyze R- and S-ketoprofen concentrations in plasma after oral (PO) and intra muscular (IM) routes of administration, and to assess the relative bioavailability of racemic ketoprofen for both enantiomers between those routes of administration in growing pigs. Methods Eleven pigs received racemic ketoprofen at dose rates of 4 mg/kg PO and 3 mg/kg IM in a randomized, crossover design with a 6-day washout period. Enantiomers were separated on a chiral column and their concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated and relative bioavailability (Frel) was determined for S and R –ketoprofen. Results S-ketoprofen was the predominant enantiomer in pig plasma after administration of the racemic mixture via both routes. The mean (± SD) maximum S-ketoprofen concentration in plasma (7.42 mg/L ± 2.35 in PO and 7.32 mg/L ± 0.75 in IM) was more than twice as high as that of R-ketoprofen (2.55 mg/L ± 0.99 in PO and 3.23 mg/L ± 0.70 in IM), and the terminal half-life was three times longer for S-ketoprofen (3.40 h ± 0.91 in PO and 2.89 h ± 0.85 in IM) than R-ketoprofen (1.1 h ± 0.90 in PO and 0.75 h ± 0.48 in IM). The mean (± SD) relative bioavailability (PO compared to IM) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively. Conclusions Although some minor differences were detected in the ketoprofen enantiomer concentrations in plasma after PO and IM administration, they are probably not relevant in clinical use. Thus, the pharmacological effects of racemic ketoprofen should be comparable after intramuscular and oral routes of administration in growing pigs.
    Acta Veterinaria Scandinavica 09/2012; 54(1). DOI:10.1186/1751-0147-54-55 · 1.38 Impact Factor
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    • "Chiral inversion of ketoprofen from the R-to the S-enantiomer has been demonstrated for several species, and there are substantial species differences in the extent of inversion e.g. 6% in sheep (Arifah et al., 2001), 15% in cats (Lees et al., 2003), 15% in goats (Arifah et al., 2003), 31% in calves (Landoni & Lees, 1995a), 49% in horses (Landoni & Lees, 1996) and 79% in rats (Iwakawa et al., 1991). "
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    ABSTRACT: Fosse, T.K., Horsberg, T.E., Haga, H.A., Hormazabal, V., Ranheim, B. Enantioselective pharmacokinetics of ketoprofen in piglets: the significance of neonatal age. J. vet. Pharmacol. Therap.34, 153–159. Following intravenous dose of 6 mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21 days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3–276.5) mL/kg and 155.0 (138.7–173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3–334.2) mL/kg and 193.0 (168.7–220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0–1171.2) mL/h/kg and 425 (319.1–566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6–70.4) mL/h/kg and 33.8 (27.0–42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4 h for both age groups, while the elimination half-life of R-ketoprofen was 0.2 h for the 6-day-old and 0.4 h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.
    Journal of Veterinary Pharmacology and Therapeutics 04/2011; 34(2):153-9. DOI:10.1111/j.1365-2885.2010.01205.x · 1.19 Impact Factor
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