Comparison of tobramycin nephrotoxicity in young adult and aged female rats.
A two week toxicity study was performed in rats to study the possible age-dependent toxicity of tobramycin, an aminoglycoside antibiotic with well known ototoxic and nephrotoxic properties in animals and man. Young adult female Wag/Rij rats aged 12 weeks (n = 10) and old female rats aged 23 to 26 months (n = 14) were treated subcutaneously with 0, 10, 40 or 160 mg tobramycin sulphate/kg/day. Clinical chemistry and urinalysis revealed significant changes in renal function in young adult rats mainly at 160 mg/kg, whereas in old rats significant changes were seen at 10, 40 and 160 mg/kg. Excretion of N-acetyl-beta-glucosaminidase, indicative for tubular dysfunction, was statistically significantly increased only in old animals at 160 mg/kg. Histopathology: At 40 mg/kg, tubular necrosis was increased in old animals and hyaline droplet formation in both age groups. At 160 mg/kg these lesions were increased in both age groups. For tubulonephrosis, interstitial nephritis and tubular regeneration, age-related differences were predominantly reflected in severity, for example, at 40 mg/kg, tubular regeneration in young animals was "moderate" in 7/10 and "marked" in 2/10, while in old animals the scores were 3/14 and 11/14, respectively. Secondary treatment-related lesions (in heart and adrenals) were also more increased in old animals. Chemistry and histopathology revealed the increased sensitivity to the toxic effects of tobramycin in old rats, which is important for the discussion of the most appropriate dosing regimen for aminoglycoside in humans. The once-daily dosing regimen for tobramycin should not be recommended for elderly, because high peak concentrations should be avoided to minimise nephrotoxicity.
Peters-Volleberg
G W
GW
Laboratory for Medicines and Medical Devices, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. trudi.peters@rivm.nl
Dortant
P M
PM
Speijers
G J
GJ
D000367:Age Factors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D014031:Tobramycin / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D014031:Tobramycin