Pharmacokinetic/pharmacodynamic evaluation of cimicoxib following two oral dosing rate in sheep

Sheep, both, breeding or used as experimental models, are often submitted to painful procedures and treated with analgesics. However, knowledge about pharmacokinetic/pharmacodynamic (PK/PD) features of analgesic drugs in this species is poor. This study was aimed to evaluate the pharmacokinetics of cimicoxib and the ex vivo COX inhibition by the drug after oral administration in sheep. Six healthy adult sheep were randomly divided into two groups and treated with two oral doses of cimicoxib (4 and 6 mg/kg) according to a crossover scheme (2X2 Latin square). Blood samples were collected at prefixed time points and aliquoted for pharmacokinetic and ex vivo studies. The analytical determination of cimicoxib in plasma was performed by HPLC with fluorescence detector, while the COX inhibition by ELISA kits. The drug absorption was widely variable among the subjects. The first detectable drug plasma concentrations were found in the range 0.25-4h. Maximal plasma concentration ranged from 189.0 to 567.3ng/mL and from 308.3 to 822.6 ng/mL following administration of cimicoxib at 4 and 6 mg/kg, respectively. The peak of concentration was achieved between 4 and 10 hours (mean= 6.7 hours) and between 6 and 10 hours (mean = 7.8 hours) in the 4 and 6 mg/kg groups, respectively; this variability was probably due to a different cimicoxib dilution in the rumen. Preliminary investigations on cimicoxib ability to inhibit the COX suggested that this drug seems not to be a COX-2 selective inhibitor in the sheep. This is in agreement with a recent study in the horse.