Influence of dosage regimen on experimental tobramycin nephrotoxicity. A biochemical approach

Many factors play a role in aminoglycoside nephrotoxicity. To study the influence of dosage regimens, Wistar rats were injected for 8 days with a total daily dose of 10, 20, or 50 mg/kg tobramycin intraperitoneally either in one single (1) or in thrice (3) daily injections. The results were different according to the dose. With 10 or 20 mg/kg, serum creatinine did not increase. Alanine aminopeptidase activities decreased whatever the rhythm of administration. gamma-Glutamyl-transpeptidase and N-acetyl-beta-D-glucosaminidase activities were unchanged. Sphingomyelinase and cathepsin B activities were diminished with three injections and not affected with one injection. Renal tobramycin content was not significantly different with (1) or with (3). Lysosomal structural latency was decreased in rats treated three times a day. With 50 mg/kg, serum creatinine was significantly increased and was higher with one injection daily. Alanine aminopeptidase decreased with only one injection daily and gamma-glutamyl-transpeptidase was unchanged. N-acetyl-beta-D-glucosaminidase was increased with (1) and with (3). Sphingomyelinase and cathepsin B activities were significantly decreased. No differences were observed in rats treated once or thrice daily. Renal tobramycin content was similar with (1) and (3). The lysosomal structural latency was significantly decreased and to the same degree for both regimens. In conclusion, based on this study and on other related studies in the literature it is presently very difficult to determine the real relationship between dosage frequency and development of nephrotoxicity.