Effect of aging on gentamicin nephrotoxicity and pharmacokinetics in rats

In humans a higher incidence of renal toxicity is seen in old than in young patients undergoing gentamicin therapy. To investigate whether the sensitivity of the old kidney to gentamicin is a function of age, separate from the adverse effects arising from declining renal excretory function, the nephrotoxicity of 12 daily injections of this antibiotic was measured in rats. Young (7-10 months) and old (25-28 months) rats, selected for minimal age-related nephropathy, received an initial dose of 30 or 50 mg of gentamycin/kg. Based on the plasma half-lives, subsequent doses for the high dose group were reduced as needed to equalize renal exposure to gentamicin. Urinary excretion of beta-galactosidase peaked by the second or third day of injections, while proteinuria was highest in the second week. The amount of microscopic renal tubular damage was dose-related and was greater in the old rats of each dose group. The increased sensitivity of old kidneys toward gentamycin toxicity, although small, thus appears to be in addition to any age-related decrease in renal elimination of the drug from plasma.