Dose response studies of gentamicin nephrotoxicity in rats with experimental renal dysfunction. III. Effects of dosage adjustment method.

Previous studies indicate that while Sprague-Dawley (SD) rats with pre-existing renal insufficiency were resistant to gentamicin nephrotoxicity, beagle dogs with renal dysfunction were sensitive. In this study the effects of gentamicin dose reduction method on nephrotoxicity were investigated in subtotally (approx. 65%) nephrectomized (Nx) SD rats. Thirty SD rats were assigned as controls (Ctrls, n = 10) or Nx (n = 20). All rats received gentamicin for 7 days. Nx rats received either a decreased dose, fixed interval (FI) or increased interval, fixed dose (FD) regimen to compensate for prior renal insufficiency. Pre- and post-dosing serum creatinine and urea nitrogen (SCr, SUN), adjusted SCr and SUN ([postdosing-predosing]/predosing), histopathologic scores and single-dose pharmacokinetic parameters were determined in all rats. Adjusted SCr and Sun values, as well as histopathology scores were consistently greater in FI rats than in FD rats. Additionally, FI rats had significantly greater predicted trough gentamicin levels than Ctrl or FD rats. The relatively lower nephrotoxicity in the FD regimen in rats agrees with results previously reported in dogs, thus indicating that the method of dose reduction in patients with compromised renal function may be a significant factor in lowering nephrotoxic potential. In addition, the subtotal Nx rat may thus be a valuable and economical model for assessing the nephrotoxicity of different drug dosage regimens in pre-existing renal disease.