Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats

Abstract

The mechanism by which endotoxin (lipopolysaccharide [LPS]) modifies the intrarenal distribution and the nephrotoxic potential of gentamicin is unknown. We studied the influence of LPS on the intracortical accumulation kinetics of gentamicin in rats infused intravenously for 6 h, during which time steady-state levels of the antibiotic in serum were achieved. We compared gentamicin accumulation rates (V) in normal rats and in rats receiving LPS (0.5 and 5 mg/kg) as levels in serum (S) varied from 0.5 to 130 micrograms/ml. The pharmacokinetic parameters of gentamicin were previously measured in the three groups of rats that were studied in order to reach and maintain in each rat the desired levels of antibiotic in serum during the 6 h of infusion. Two hours before the infusion of gentamicin, LPS was injected intravenously over a period of 15 min. In normal rats, the increase in S was associated with a nonlinear increase in V. The Michaelis-Menten kinetics, which was the best-fitting function, gave an apparent Vmax (maximal capacity of uptake) of 195.03 +/- 9.75 micrograms/g per h and an apparent Km (concentration in serum at Vmax/2, an index of affinity) of 34.91 +/- 4.45 micrograms/ml (linear transformation of the experimental data by the Hanes-Woolf plot: r = 0.93, n = 85). In the rats that received LPS, the increase in S was associated with a linear increase of V: for LPS at 0.5 mg/kg, V = 27.00 + 1.50 S (r = 0.94, n = 80); for LPS at 5 mg/kg, V = 22.72 + 1.48 S (r = 0.94, n = 75). We conclude that endotoxin modifies the accumulation kinetics of gentamicin in the kidney cortices of rats.