The effect of dosing strategy on kidney cortical accumulation of aminoglycosides in rats

The influence of three different dosage schedules on kidney cortical accumulation of aminoglycosides was studied in rats. A daily dose of 10 mg/kg of gentamicin or tobramycin or 33.3 mg/kg of amikacin were given, either in single injections, three injections eight hours apart, or by continuous infusion. Kidney cortical levels of aminoglycosides were examined at regular intervals up to eight days. The pattern for cortical accumulation under different dose regimens was drug-dependent. Continuous infusion of gentamicin resulted in remarkably higher cortical concentrations than after intermittent administrations. In contrast, cortical levels of tobramycin were independent of the regimen used. For amikacin, higher accumulation resulted from continuous administration from the second day. However, the differences in tissue levels after one or the other dose regimen were less striking than for gentamicin. These observations were explained by differences in cortical uptake kinetics for aminoglycosides previously reported. Elevations in serum concentrations of gentamicin were associated with nonlinear uptake. Accordingly, uptake of gentamicin is more "efficient" at low serum concentrations. Uptake of tobramycin was linearly related to increases in serum levels. Amikacin showed a mixed kinetics pattern, saturation at low serum levels, and linear kinetics at high serum concentrations. This explains the higher cortical levels reached with continuous infusion of amikacin compared with intermittent administration. Uptake kinetics play an essential role in cortical aminoglycoside concentrations achieved after different dosing strategies. The design of regimens minimizing cortical uptake may decrease the risk of nephrotoxicity.