Effect of probenecid on the pharmacokinetics of cefotaxime in sheep

The effect of probenecid given by intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection on the pharmacokinetics of cefotaxime was studied in six Merino ewes. When given intravenously, probenecid increased significantly (P less than 0.05) the plasma half-life of cefotaxime three-fold (to 0.94 +/- 0.32 h) and the area under the curve (AUC) approximately two-fold (to 41.1 +/- 16.8 micrograms.h/ml), and decreased plasma cefotaxime clearance (ClB) 45% (to 0.648 +/- 0.191 l/h/kg). When given with probenecid intravenously, renal clearance (ClR), volume of the central compartment (VC), volume of distribution steady state (Vd(ss], and the amount excreted in urine unchanged did not alter significantly. When given by i.m. injection, probenecid and cefotaxime were well tolerated and cefotaxime was well absorbed (101 +/- 45%). When given by s.c. injection, only 40 +/- 25% cefotaxime was absorbed. When given intramuscularly or subcutaneously, probenecid appeared to reduce the ClB and ClR of cefotaxime, probably because plasma probenecid concentrations are prolonged. Probenecid did not appear to affect the distribution of cefotaxime.