Study on pharmacokinetics and nephrotoxicity of netilmicin in rabbits using a new dosage regimen

The potential nephrotoxicity and pharmacokinetic parameters of netilmicin were investigated in rabbits after single and multiple dosage regimens (7 mg/kg/12 h) allometrically equivalent to a once-daily regimen of 5 mg/kg/24 h in man. Netilmicin was determined in plasma and renal tissue by a high-performance liquid chromatography (HPLC) technique with fluorescence detection and precolumn derivatization. The renal toxicity was determined by electron microscopy. Statistical comparison between animals that received a single dose and those that received a multiple dosage regimen showed that the only parameter significantly different was the elimination constant K10. The histological study revealed a high interindividual variability in the nephrotoxicity induced by prolonged treatment with netilmicin: 50% of the animals experienced tubular necrosis and the remaining did not. Although plasma concentration time curves did not show significant differences between both groups of animals, the concentrations of netilmicin in renal cortex were higher in the group with tubular necrosis. In conclusion, even though netilmicin was administered in a dosage regimen equivalent to once-daily administration in man, it induced tubular necrosis which was probably related to the duration of treatment. The results also showed that there was no correlation between plasma concentrations of the drug and its potential nephrotoxicity.