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Nephrotoxicity of amphotericin B in rats: effects of the time of administration
M LeBrun1, L Grenier, P Gourde
1Laboratoire et Service d'Infectiologie, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, Canada.
Abstract:
Amphotericin B is a potentially nephrotoxic agent used for the treatment of severe mycoses and numerous fungal infections. Temporal variation in the nephrotoxicity of amphotericin B was studied in rats maintained on a light-dark period of 14 hrs of light and 10 hrs of darkness (light on: 06h00). Subgroups of animals were treated with a single daily i.p. dose of either 5% dextrose or amphotericin B (10 mg/kg/day) given at either 07h00, 13h00, 19h00 or 01h00 for 4 and 10 days. On day 4, no significant difference was observed in any parameter studied. On day 10, the cellular regeneration ([3H]-thymidine incorporation into DNA of renal cortex)(p<0.01), BUN levels (p<0.05), serum creatinine (p<0.05), and accumulation of amphotericin B in the renal cortex (p<0.05) were significantly higher when animals were treated with similar subcellular localization of amphotericin B in the proximal tubular cells of the renal cortex. These results showed a temporal variation in the nephrotoxicity of amphotericin B (peak toxicity occurred at 07h00) which is different from that of other nephrotoxic antibiotics such as aminoglycosides.
Insights
Amphotericin B
Area of Science:
- Pharmacology
- Toxicology
- Chronobiology
Background:
- Amphotericin B is a critical antifungal medication for severe mycoses.
- Its use is limited by potential nephrotoxicity.
- Understanding temporal factors influencing toxicity is crucial for patient safety.
Purpose of the Study:
- To investigate the temporal variation in amphotericin B-induced nephrotoxicity.
- To determine if the timing of drug administration affects kidney damage.
- To compare the chronotoxicity of amphotericin B with other nephrotoxic antibiotics.
Main Methods:
- Rats were administered amphotericin B (10 mg/kg/day) or dextrose at different times (07h00, 13h00, 19h00, 01h00) for 4 and 10 days.
- Kidney function markers (BUN, serum creatinine) and renal cortex cellular regeneration ([3H]-thymidine incorporation) were assessed.
- Amphotericin B accumulation in the renal cortex was quantified.
Main Results:
- No significant differences in nephrotoxicity were observed on day 4.
- On day 10, significant increases in cellular regeneration, BUN, serum creatinine, and amphotericin B accumulation occurred.
- Peak nephrotoxicity and drug accumulation were observed when amphotericin B was administered at 07h00.
Conclusions:
- Nephrotoxicity of amphotericin B exhibits temporal variation in rats.
- Administration timing significantly impacts amphotericin B-induced kidney damage, with morning administration (07h00) showing peak toxicity.
- This chronotoxicity profile differs from that of aminoglycoside antibiotics.