Comparison of Tobramycin Nephrotoxicity in Young Adult and Aged Female Rats

Abstract

Abstract; 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 WagiRij 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 mgikg, whereas in old rats significant changes were seen at 10, 40 and 160 mgi kg. Excretion of N-acetyl-p-glucosaminidase, indicative for tubular dysfunction, was statistically significantly increased only in old animals at 160 mg/kg. Histopcithobgj? At 40 mg/kg, tubular necrosis was increased in old animals and hyaline droplet formation in both age groups. At 160 mgikg 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 mgikg, 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. Secundary 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 tobrdniycin 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.In the human population a number of subpopulations can be discerned with a higher sensitivity to toxic side-effects of pharmaceuticals than the general population. For example elderly people, a group of people which will increase markedly in the near future. Knowledge is insufficient about the possible greater sensitivity to toxicants and therapeutic drugs of both elderly people and older animals (IPCS 1993).Risk assessment is usually based on experiments in young adult healthy test animals, so this study was initiated to determine possible age-related differences in response to tobramycin between young adult and old animals.In the present study, young adult and old female rats were exposed to the aminoglycoside antibiotic, tobramycin, as a model compound to study possible age-related differences in toxic effects. Aminoglycosides are widely used for the treatment of Gram-negative infections. Serious limitation to the use of these drugs are due to the major side effects, ototoxicity and nephrotoxicity. Nephrotoxicity is significantly higher in older humans and animals (McMartin & Engel 1982; Provoost et ul. 1985;Ali 1995; Ali et al. 1996). Female rats were chosen for two reasons, first, they d o not excrete male rat-specific small molecular proteins, like ct2u globulin, which can accumulate in the renal proximal...

Histiocytic Sarcoma in C57BL/6J Female Mice is Associated with Liver Hematopoiesis: Review of 41 Cases

“…However, as Ward et al (23), we do not retrieve such an association with HS, though the disease is often widespread in our 41 mice. In addition, the signification of the frequency of renal hyaline droplets in our control group remains elusive, as such droplets are otherwise mentioned only in nephrotoxicity studies (15,17,24).…”

The Aging Kidney: Increased Susceptibility to Nephrotoxicity

“…These ex vivo studies again demonstrated that the proximal tubular epithelial cells had an inherent increase in susceptibility to injury. Aged Wag/Rij rats (23–26 months) are more sensitive to tobramycin, an aminoglycoside antibiotic, as evidenced by tubular necrosis and urinary NAG levels [ 45 ]. More recent studies have extended age-dependent AKI models to the mouse.…”

Does once-daily dosing prevent nephrotoxicity in all aminoglycosides equally?

“…The duration of aminoglycoside therapy, with a cut‐off point at 6 or 7 days, and the cumulative dose are recognized in both uni‐ and multivariate analysis as strong and well documented toxicity factors even if individualized pharmacokinetic monitoring is used [10–22]. High serum peak concentrations in the very elderly population, and administration of aminoglycosides during patients' rest periods, may also favor nephrotoxicity [23–25].…”