Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

Abstract

The kinetics of aminoglycoside binding to renal brush border and basolateral membrane vesicles from rat renal cortex were studied by using [3H]amikacin. [3H]amikacin binding to renal membranes was found to be a rapid, saturable process with a fourfold greater affinity for basolateral membranes than for brush border membranes (Kd basolateral = 607 microM; Kd brush border = 2,535 microM). Renal membranes prepared from immature rats (2 to 3 weeks old) exhibited a significantly lower affinity compared with membranes from adults (Kd basolateral = 2,262 microM; Kd brush border = 6,216 microM). Additionally, the inhibitory behavior of several aminoglycosides versus [3H]amikacin binding to brush border membranes revealed the following rank order of potency: neomycin greater than tobramycin approximately gentamicin approximately netilmicin greater than amikacin approximately neamine greater than streptomycin. The relative insensitivity of immature rats to aminoglycoside-induced nephrotoxicity in vivo and the comparative nephrotoxicity of the various aminoglycosides suggest that renal membrane-binding affinity is closely correlated to the nephrotoxic potential of these antibiotics.