Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs

Abstract

BackgroundKetoprofen 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.MethodsEleven 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.ResultsS-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.ConclusionsAlthough 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.

Comparative Plasma and Interstitial Fluid Pharmacokinetics of Meloxicam, Flunixin, and Ketoprofen in Neonatal Piglets

“…However, the R(+)-ketoprofen enantiomer may be a more potent analgesic according to a study assessing mechanical nociceptive threshold (21). In many species, S(-)-ketoprofen predominates over R(+)-ketoprofen in terms of plasma exposure following intramuscular administration of racemic ketoprofen (22,(37)(38)(39). The current study also found this to be true in piglets, and additionally found that this was also true for interstitial fluid exposure.…”

“…It is additionally important to consider the stereoselective pharmacokinetics of ketoprofen, rather than simply total ketoprofen concentration, as plasma concentration and pharmacodynamic effect of each enantiomer differs between species (37). Previous studies in pigs have reported that the S(-)-enantiomer is a more potent cyclooxygenase-inhibitor, and therefore displays greater anti-inflammatory effects compared to the R(+)-enantiomer (22,38).…”

Randomised trial of the bioavailability and efficacy of orally administered flunixin, carprofen and ketoprofen in a pain model in sheep

“…31 Maximum concentrations were 7.42 mg/L for S-ketoprofen and 2.55 mg/L for R-ketoprofen when administered orally in pigs. 32 The concentration of ketoprofen in plasma was 4.5-8.4 μg/mL in our sheep at 2 h after administration and R-ketoprofen has been recorded as the most prominent enantiomer found in sheep. 17 Based on these results, oral administration of the three NSAIDs at twice the standard parental dose shown to be therapeutic in other species was expected to be still within the therapeutic range for sheep; however, it is recommended that work should be done to identify the therapeutic levels in sheep.…”

Enantioselective pharmacokinetics of ketoprofen in calves after intramuscular administration of a racemic mixture

“…The intravenous (i.v.) or extravascular administration of racemic KTP demonstrated enantioselective PK in sheep, camels, pigs, horses, dogs, cats and poultry, with a predominance of the S(+) enantiomer in plasma of most species, except for sheep, camels and poultry, in which R(−) KTP predominated (Delatour et al ., ; Jaussaud et al ., ; Landoni & Lees, ; Landoni et al ., ; Al Katheeri et al ., ; Arifah et al ., ; Lees et al ., ; Fosse et al ., ; Neirinckx et al ., ; Mustonen et al ., ). In contrast, the i.v.…”