Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma, exudate and transudate in sheep

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t(1/2 beta)) of 2.48 +/- 0.12 h and an area under the concentration - time curve (AUC) of 30.61 +/- 3.41 mu g/mL.h. Elimination of PBZ from plasma was slow (t(1/2 beta) = 17.92 +/- 1.74 h, AUC = 968.04 +/- mu g/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (C-max) for FM of 1.82 +/- 0.22 mu g/mL at 5.50 +/- 0.73 h (exudate) and 1.58 +/- 0.39 mu g/mL at 8.00 h (transudate), and C-max for PBZ of 22.32 +/- 1.29 mu g/mL at 9.50 +/- 0.73 h (exudate) and 22.07 +/- 1.57 mu g/mL at 11.50 +/- 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUC(last) ratio obtained in the FM and PBZ groups (80-98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.