Ketoprofen in the Cat: Pharmacodynamics and Chiral Pharmacokinetics

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.

Stereoisomeric profiling of pharmaceuticals ibuprofen and iopromide in wastewater and river water, China

“…Many pharmaceuticals are chiral compounds with one or more chiral centers. In spite of identical chemicalphysical properties, enantiomers of pharmaceuticals usually differ in their biological properties, leading to differences in their biological effects, such as toxicity and biotransformation (Lees et al 2003;Knoche and Blaschke 1994;Qian et al 2009). Thus, chiral pharmaceuticals in the environment may experience stereoisomer-specific behavior (Buser et al 1999;Fono and Sedlak 2005;MacLeod and Wong 2010;Nikolai et al 2006;Wong 2006) and exhibit stereoisomer-specific ecotoxicity (Stanley et al 2009).…”

Pain management in cat

“…Η κετοπροφαίνη είναι μη ειδικός αναστολέας της COX (Lees et al 2003). Στον άνθρωπο αναφέρεται ότι αναστέλλει εν μέρει και τη λιποοξυγονάση, με συνέ πεια τη μεγαλύτερη αποτελεσματικότητα λόγω μειω μένης παραγωγής λευκοτριενίων (Sigurdsson and Youssef 1994).…”

Comparison of Gastrointestinal Adverse Effects of Ketoprofen between Adult and Young Cats

“…Ketoprofen bioavailability in cats has been reported as 112 and 85% for S(+) and R(−) ketoprofen, respectively [14]. However, this value of bioavailability for S(+) ketoprofen may be an overestimate because of inversion of R(−) to S(+) ketoprofen.…”

“…However, this value of bioavailability for S(+) ketoprofen may be an overestimate because of inversion of R(−) to S(+) ketoprofen. Nevertheless, the percentage absorption of R(−) and S(+) ketoprofen seems relatively high [14]. For many NSAIDs, glucuronidation is an important pathway.…”