Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep

Abstract

Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four-way, four-period cross-over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half-life (t1/2KeO) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.

Early detection of ketoprofen-induced acute kidney injury in sheep as determined by evaluation of urinary enzyme activities

“…The elimination half-life of ketoprofen in plasma was higher after the overdose of ketoprofen in the sheep of the present study than in sheep in other studies 25,26 after administration of a frequently used dose of racemic ketoprofen (3 mg/kg) or its enantiomers. Approximately 2 hours after administration of ketoprofen at a dose of 30 mg/kg, the plasma concentration of ketoprofen in our study was at the same value as the maximum concentration reported in sheep after administration at the frequently used dose of 3 mg/kg.…”

“…Approximately 2 hours after administration of ketoprofen at a dose of 30 mg/kg, the plasma concentration of ketoprofen in our study was at the same value as the maximum concentration reported in sheep after administration at the frequently used dose of 3 mg/kg. 25,26 Thus, exposure to the toxic plasma concentration of ketoprofen was probably relatively short, and most of the injuries in the tubular cells can be expected to have taken place during the early phase of our follow-up period.…”

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

“…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.…”

“…There were four treatment groups: carprofen (8.0 mg/kg, PiaPharma, NSW, Aust), ketoprofen (8.0 mg/kg, PiaPharma), flunixin (4.0 mg/kg, PiaPharma) and saline (Baxter, NSW, Aust) daily for the 6 days of the trial. Dose rates were based on doses of these NSAIDs given to sheep in previous experiments, 16,17 but doubled because of the rumen's potential to reduce bioavailability. All the treatment groups were given their assigned treatment orally as a solution by syringe to the back of the tongue.…”

“…The pharmacokinetics of NSAIDs such as carprofen, ketoprofen and flunixin have been well documented in cattle, [10][11][12] horses 13,14 and sheep. [15][16][17] There are reports describing the efficacy of NSAIDs to alleviate pain in sheep when administered via subcutaneous, intramuscular and intravenous routes. 4,18 Carprofen is a long-acting analgesic with a half-life >30 h in sheep 16 and has been shown to reduce pain-related behaviours in lambs that have undergone mulesing and castration.…”