Heat treatment of amphotericin B modifies its serum pharmacokinetics, tissue distribution, and renal toxicity following administration of a single intravenous dose to rabbits

The purpose of this investigation was to determine the serum pharmacokineti cs, tissue distribution, and renal toxicity of amphotericin B (AmpB) follow ing administration of a single intravenous dose (1 mg/kg of body weight) of Fungizone (FZ) and a heat-treated form of FZ (HFZ) to New Zealand White fe male rabbits. FZ solutions were heated at 70 degreesC for 20 min to produce HFZ. Blood samples were obtained before drug administration and serially t hereafter. After collection of the 48-h blood sample, each rabbit was human ely sacrificed and the right kidney, spleen, lungs, liver, and heart were h arvested for AmpB analysis. Serum creatinine levels were measured before an d 10 h after drug administration. AmpB concentrations in the serum and tiss ues were analyzed using high-performance liquid chromatography. FZ administ ration to rabbits resulted in a greater-than-50% increase in serum creatini ne concentrations compared to baseline. However, HFZ administration resulte d in no difference in serum creatinine concentrations compared to baseline. The AmpB area under the concentration-time curve (AUC) after HFZ administr ation was significantly lower than the AmpB AUC in rabbits administered FZ. However, AmpB systemic total body clearance was significantly greater in r abbits administered HFZ than in rabbits administered FZ without any differe nces in volume of distribution at steady state. Kidney tissue AmpB concentr ations, although not significantly different, were greater in rabbits admin istered FZ than in rabbits administered HFZ. Likewise, lung and spleen AmpB concentrations, although not significantly different, were greater in rabb its administered FZ than in rabbits administered HFZ. However, liver AmpB c oncentrations were significantly lower in rabbits administered FZ than in r abbits administered HFZ. No significant differences in heart AmpB concentra tion between rabbits administered PZ and those given HFZ were found. These findings suggest that the pharmacokinetics, tissue distribution, and renal toxicity of AmpB are modified following administration of HFZ, HFZ could be an improved low-cost AmpB drug delivery system that has a potentially high er therapeutic index than FZ.