A PHARMACOKINETIC STUDY OF GENTAMICIN SULFATE IN RABBITS WITH HYDRONEPHROSIS

Abstract

The pharmacokinetics of gentamicin sulfate (GM) have been investigated in rabbits with unilateral or bilateral hydronephrosis. An experimental model of hydronephrosis was produced by an incomplete ligation of the ureter at a lower portion, and 5mg/kg of GM was intravenously injected 7 days after ligation. GM concentrations in serum, urine and renal tissue were measured by substrate-labeled fluorescent immunoassay. The pharmacokinetic parameters of GM were obtained by analyzing the serum levels of GM on the basis of a two-compartment open model. In rabbits with bilateral hydronephrosis, the elimination rate constant, β-phase rate constant and total body clearance decreased, serum half-life (β) was prolonged, and the area under the curve of serum concentration increased as compared to normal control rabbits. The elimination rate constant, β-phase rate constant and total body clearance were all correlated with the creatinine clearance (p<0.01). The split renal clearance and urinary recovery of GM decreased in the hydronephrotic kidneys, and increased in the intact kidneys of rabbits with unilateral hydronephrosis. The split renal clearance and urinary recovery were correlated with the creatinine clearance of the individual kidney (p<0.01), respectively. The urinary concentration of GM in the hydronephrotic kidneys decreased with the lowering of urinary concentrating ability. Renal cortical and medullary concentrations of GM decreased in the hydronephrotic kidneys, and the renal cortical concentrations were correlated with the creatinine clearance and cortical blood flow of the individual kidney (p<0.01), respectively.
These experimental results suggest that proper doses and administration intervals for GM should be adopted on the basis of the creatinine clearance in individual cases with hydronephrosis in order to maintain therapeutic and nontoxic serum levels of GM. Since GM levels in the tissue of the hydronephrotic kidneys were lower than those of the contralateral intact kidneys, GM administration taking into account split renal function should be utilized in cases with hydronephrosis.