Influence of hydrocortisone succinate on intrarenal accumulation of gentamicin in endotoxemic rats

Abstract

Gentamicin is a commonly used antibiotic in the treatment of gram-negative infections including septicemia and pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy and may lead to endotoxemic shock. Steroids such as hydrocortisone are generally recommended in the treatment of endotoxemic shock. There are very limited data on the influence of endotoxin or corticosteroids on the pharmacology of antibiotics, especially aminoglycosides, which are nephrotoxic. We studied the influence of both Escherichia coli endotoxin and hydrocortisone succinate on the renal uptake of gentamicin in rats. Animals were injected intravenously with endotoxin (0.25 mg/kg) and/or hydrocortisone (25 mg/kg) plus gentamicin (10 mg/kg). Gentamicin levels in the serum and renal parenchyma as well as renal function and histology were evaluated. Both endotoxin and hydrocortisone given alone increased the concentration of gentamicin in the renal cortex (P less than 0.05). Normal values in serum were observed in all groups at most time intervals. When administered together, endotoxin and hydrocortisone did not potentiate each other. The combination of endotoxin and hydrocortisone gave significantly higher levels of gentamicin than endotoxin or hydrocortisone alone when endotoxin was injected 3 h before hydrocortisone (P less than 0.05). Blood pressure and cardiac frequency were normal when gentamicin was given. Endotoxin alone slightly decreased the glomerular filtration rate, and hydrocortisone alone slightly modified renal plasma flow. The combination of both drugs did not significantly affect renal function. No histological lesion was noted on light microscopy in animals receiving endotoxin. Competitive or synergistic activity of endotoxin, gentamicin, and hydrocortisone at the cellular level, especially on membranes or lysosomes, might explain in part our observation on the renal uptake of gentamicin. By increasing the total amount of drug within the kidney, endotoxin and hydrocortisone might increase the risk of nephrotoxicity associated with aminoglycosides.