INFLUENCE OF A BACTERIAL LIPOPOLYSACCHARIDE ON THE PHARMACOKINETICS OF TOBRAMYCIN IN RATS

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the rena l handling and distribution characteristics of the aminoglycoside tobr amycin were investigated in rats. Tobramycin (2 mg kg(-1)) and inulin (100 mg kg(-1)) were administered intravenously 2 h after administrati on of 50, 250 or 500 mu g kg(-1) lipopolysaccharide. Lipopolysaccharid e delayed the disappearance of tobramycin from plasma in a dose-depend ent manner. A dose-dependent decrease in systemic clearance of tobramy cin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influenc e the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartme nt to the rate constant of transfer from peripheral compartment to cen tral compartment was observed. The glomerular filtration rate was sign ificantly decreased by pretreatment with 250 mu g kg(-1) lipopolysacch aride and the clearance ratio was decreased by 20%, indicating that li popolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies th e glomerular filtration rate and tubular reabsorption without change i n the terminal half-life and that drug distribution characteristics fr om the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.