The purpose of this investigation was to study the pharmacokinetics and nephrotoxicity of amphotericin B (AmB), incorporated in poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) (PEG-b-PHSA) micelles (AmB/PEG-b-PHSA). After AmB/PEG-b-PHSA or AmB for injection, United States Pharmacopeia (USP), was dosed intravenously in rats (0.8 mg/kg), serum was collected over 72 h, and organs collected at 72 h for AmB analysis. To test for the nephrotoxicity caused by AmB, renal markers of damage were assessed 24 h after a single injection of AmB/PEG-b-PHSA or AmB for injection, USP, focusing on detection of urinary enzymes. PEG-b-PHSA micelles caused a significantly lower area under serum concentration curve and higher clearance relative to AmB for injection, USP. PEG-b-PHSA micelles lowered the distribution of AmB in liver and lung tissues, but did not significantly lower the level of AmB in the kidneys relative to AmB for injection, USP. However, urine levels of N-acetyl-β-glucosaminidase and γ-glutamyltransferase were significantly lower for AmB/PEG-b-PHSA relative to AmB for injection, USP. In summary, PEG-b-PHSA micelles reduced the nephrotoxicity of AmB, the dose-limiting toxicity of this important antifungal agent.
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