Ketoprofen in the cat: Pharmacodynamics and chiral pharmacokinetics

University of Cambridge, Cambridge, England, United Kingdom
The Veterinary Journal (Impact Factor: 2.17). 02/2003; 165(1):21-35. DOI: 10.1016/S1090-0233(02)00168-5
Source: PubMed

ABSTRACT 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
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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: Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days 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 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h 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 · 1.32 Impact Factor
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    • "The rapid gastrointestinal motility of quail may also have reduced the oral bioavailability of ketoprofen (Roder et al., 1996; Cristofol et al., 2000). Multiple studies have demonstrated that in many different species pharmacokinetic and pharmacodynamic differences exist between the R()) and S()) enantiomers of ketoprofen (Arifah et al., 2001; Navarre et al., 2001; Lees et al., 2003) In order to demonstrate these differences, the use of enantioselective methods for the analysis of R()) and S()) ketoprofen in biological fluids has become common practice. However, in this study a nonenantioselective method was used for determination of total serum ketoprofen concentrations. "
    Journal of Veterinary Pharmacology and Therapeutics 09/2005; 28(4):399-402. DOI:10.1111/j.1365-2885.2005.00673.x · 1.32 Impact Factor
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    ABSTRACT: Les effets anti-inflammatoires et analgésiques des AINS s'expliquent en grande partie par leur capacité à inhiber l'activité cyclo-oxygénase sur le site inflammatoire. Il est possible qu'ils exercent au niveau central une action de même nature. La cyclo-oxygénase possède deux isoenzymes : COX-1 et COX-2. Il est admis que la plupart des effets indésirables des AINS résultent de l'inhibition de l'activité COX-1 ; c'est pourquoi la tendance actuelle est au développement d'AINS inhibant préférentiellement COX-2. Néanmoins, tous les AINS présentent des risques identiques pour la fonction rénale. Pendant longtemps, les propriétés analgésiques des AINS ont surtout été utilisées pour traiter la douleur chronique d'origine arthrosique. Actuellement, leurs conditions d'utilisation se sont largement étendues. Ils se sont ainsi montré tout particulièrement efficaces pour traiter entre autre la douleur post-opératoire. Les AINS peuvent être utilisés seuls ou faire partie d'un protocole d'analgésie multimodale.
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