Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep

The pharmacokinetics of diclofenac was investigated in sheep given diclofenac alone (1 mg kg−1, i.v. or i.m.) and in combination with enrofloxacin (5 mg kg−1, i.v.). The plasma concentration–time data following i.v. administration of diclofenac was best described by a two compartment open pharmacokinetic model. The elimination half-life (t1/2β), area under concentration–time-curve (AUC), volume of distribution (Vdarea), mean residence time (MRT) and total body clearance (ClB) were 1.03 ± 0.18 h, 12.17 ± 1.98 μg h ml−1, 0.14 ± 0.02 L kg−1, 1.36 ± 0.16 h and 0.10 ± 0.02 L kg−1 h−1, respectively.Following i.m. administration of diclofenac alone and in conjunction with enrofloxacin, the plasma concentration–time data best fitted to a one compartment open model. The t1/2β, AUC, Vdarea, MRT and ClB were 1.33 ± 0.10 h, 7.32 ± 1.01 μg h mL−1, 0.13 ± 0.01 L kg−1 and 0.07 ± 0.01 L kg−1 h−1, respectively. Co-administration of enrofloxacin did not affect Vdarea and MRT but absorption rate constant (Ka), β  , t1/2Kat1/2Ka, t1/2β, AUC, AUMC, ClB and bioavailability (F) were significantly increased. This may be due to direct inhibition of cytochrome P450 isozymes by enrofloxacin. A dose of 1.4 mg kg−1 of diclofenac administered every 6 h may be appropriate for use in sheep.