PHARMACOKINETIC PREDICTION OF GENTAMICIN TISSUE RESIDUES IN SHEEP: EFFECT OF DOSE, ROUTE, AND DURATION OF THERAPY

The adequate prediction of tissue drug residues in food-producing animals can improve the profitability of the livestock industry and yet assure a wholesome product for the consumer. After a 10 mg/kg intravenous (IV) dose of gentamicin, urinary clearance of gentamicin comprised approximately 80-90% of the total serum clearance (Cl(,s)). Biliary and salivary excretion accounted for \u3c1% of the dose. The renal cortex contained over 200 (mu)g of gentamicin/g. The terminal phase serum half-life was longer (P \u3c 0.01) after intramuscular (IM) administration of 3 mg/kg every 8 hours for 7 days (82 hours) than after a single 10 mg/kg IV dose (30 hours). At 1, 8, and 15 days after multiple IM dosing the renal cortex contained approximately 220 (mu)g of gentamicin/g, followed by renal medulla, liver, lung and spleen, urinary bladder, gastrointestinal tract, and cardiac and skeletal muscle. In a crossover study, as the single IV dose of gentamicin increased from 3 to 20 mg/kg, a more complex exponential curve was needed. Thus, as the dose increased, the normalized area under the curve (AUC) decreased, which caused the steady-state volume of distribution (Vd(,ss)) and Cl(,s) to increase. The terminal serum concentrations after of 3 mg/kg IV every 8 hours for 7 days were not adequately predicted by three-phase or four-phase single dose models. The final study investigated the effects of total IM dose and dosage regimen on gentamicin tissue residues. The normalized AUC decreased and V(,d(ss)) and Cl(,s) increased as the total IM dose increased from 2 to 18 mg/kg (P \u3c 0.05). The decline in renal cortical concentrations was predicted by either a biexponential equation or a power function. The power function also predicted the renal cortical concentrations in sheep from the first study and in rats from another laboratory. The fraction of the dose taken up by the kidney decreased as the dose increased from 2 to 18 mg/kg. Tissue concentrations were dependent on the total dose of gentamicin administered; tissue concentrations did not change regardless of whether the total dose of 18 mg/kg was given as a single IM dose, split into three single daily doses, or split into 9 doses at 8 hour intervals. Although variable, concentrations at the injection site were as high as 29 (mu)g/g