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Circadian variations in the renal toxicity of gentamicin in rats
C Pariat1, P Courtois, J Cambar
1Institut d'Etudes des Médicaments, U.E.R. de Médecine et de Pharmacie, Poitiers, France.
Abstract:
The hypothesis that sublethal doses of aminoglycosides cause renal tubule disorders resulting in changes of urine enzyme levels was investigated. The renal status following injection of a single sublethal dose of gentamicin (200 mg/kg) at different times during a 24 h cycle was studied. Increased excretion of gamma-glutamyl transferase, alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase, used clinically as markers for tubule toxicity of aminoglycosides, was maximal when gentamicin was administered to rats at 2 p.m. and was minimal when injected at 8 p.m. These significant differences in enzyme excretion as a function of injection time are correlated with the concentration of gentamicin in the urine and in the renal cortex.
Insights
Sublethal gentamicin doses can harm kidney tubules, altering urine enzyme levels. The timing of gentamicin administration significantly impacts the severity of this renal tubule toxicity in rats.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Aminoglycosides, like gentamicin, are potent antibiotics but can cause kidney damage.
- Sublethal doses may lead to subclinical renal tubule disorders.
- Urinary enzyme levels are sensitive indicators of kidney tubule injury.
Purpose of the Study:
- To investigate if sublethal doses of aminoglycosides induce renal tubule disorders.
- To determine if the timing of gentamicin administration affects urinary enzyme excretion and renal toxicity.
Main Methods:
- Rats received a single sublethal dose of gentamicin (200 mg/kg) at various times over a 24-hour period.
- Urinary levels of gamma-glutamyl transferase, alanine aminopeptidase, and N-acetyl-beta-D-glucosaminidase were measured.
- Gentamicin concentrations in urine and renal cortex were analyzed.
Main Results:
- Increased excretion of urinary enzymes, markers of tubule toxicity, was observed.
- The peak enzyme excretion occurred when gentamicin was administered at 2 p.m.
- Minimal enzyme excretion was noted when gentamicin was given at 8 p.m.
- Significant differences in enzyme excretion correlated with gentamicin concentration in urine and renal cortex.
Conclusions:
- The time of day for gentamicin administration influences the degree of renal tubule damage.
- Circadian variations in gentamicin pharmacokinetics or renal handling may explain the observed differences in toxicity.
- Optimizing gentamicin administration timing could potentially mitigate aminoglycoside-induced nephrotoxicity.