Title

Investigation of the renal disposition of gentamicin in the isolated, perfused rat kidney

Date of Completion

January 2000

Keywords

Health Sciences, Pharmacology|Chemistry, Pharmaceutical|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

Gentamicin remains one of the primary antibiotics used for treatment of gram-negative infections despite the known incidence of adverse effects. While several studies have investigated many facets of gentamicin induced nephrotoxicity, the aggravating cause has not been discovered. Precise knowledge of the renal handling of gentamicin is believed to provide elucidation into the mechanism of nephrotoxicity. In the present investigation, the isolated, perfused rat kidney technique was used to gain insight into the renal disposition of gentamicin. Several studies were performed including a dose range, passive reabsorption and drug interaction study. The dose range study analyzed the effect of increasing gentamicin concentration on renal function, drug elimination and drug accumulation. The reabsorption study was conducted to determine whether drug elimination varied with alterations in passive reabsorption mediated through urine flow rate. The drug interaction study employed cimetidine, a classical organic cation transport inhibitor, to determine if renal gentamicin disposition was altered by inhibiting organic cation transporters. ^ Evaluation of kidney function was determined with gentamicin concentrations ranging from therapeutic to toxic levels. Kidneys exposed to gentamicin exhibited a dose dependent decrease in glomerular filtration rate and fractional reabsorption of sodium. ^ The renal elimination mechanism of gentamicin was determined to be comprised of glomerular filtration, tubular secretion and tubular reabsorption consisting of active and passive components. Gentamicin secretion was evident once active reabsorption was inhibited. Since gentamicin secretion occurred with concomitant cimetidine administration, the process responsible for gentamicin secretion is presumed to be separate from the organic cation transport system. ^ Active reabsorption of gentamicin was saturated at high drug concentrations and was inhibited by concomitant cimetidine administration. Previous reports have disputed the likelihood of passive reabsorption across proximal tubule cell membranes. In the present study, excretion of gentamicin was affected by altering urine flow rate suggesting the presence of passive reabsorption. ^ Retention of gentamicin in kidney tissue was affected by increased gentamicin concentration and urine flow rate but unaffected by concomitant cimetidine administration. These findings suggest that the accumulation of gentamicin in the kidney is a multifaceted process involving active and passive reabsorption mechanisms. ^