Influence of Endotoxin and Lipid a on the Renal Handling and Accumulation of Gentamicin in Rats

The contribution of lipid A, an active component of endotoxin (LPS), to changes in the pharmacokinetics, renal handling and intrarenal accumulation of gentamicin induced by Klebsiella pneumoniae LPS was investigated in rats. Either LPS (250 μg/kg) or lipid A (equivalent to dose of LPS) was infused 2 h before the administration of gentamicin (10 mg/kg). The effects of LPS and lipid A on the intrarenal accumulation of gentamicin were also evaluated. Significant increases in the levels of plasma creatinine and blood urea nitrogen were observed in both the LPS and lipid A groups. Both LPS and lipid A induced significant decreases in the glomerular filtration rate (by approximately 30%) and systemic clearance of gentamicin (by approximately 25%). No changes in the fraction of urinary excretion (> 0.9) or steady-state volume of distribution of gentamicin were observed between either the control, LPS or lipid A groups. There were no significant differences among the three groups in the tubular reabsorption or intrarenal accumulation of gentamicin. The degree of effect of lipid A on the pharmacokinetics of gentamicin observed in this study was nearly equal to that of LPS. These results suggest that lipid A plays a major role in changes in the pharmacokinetics and renal handling of gentamicin induced by LPS.