Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents

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Abstract
AmBisome is a lyophilizcd preparation of lipaomal amphotericin B. The acute intravenous toxicity of AmBisome was evaluated in mice and rats; and the LD50s were found to be > 175 and 50 mg/kg, respectively. The corresponding LD50 for conventional amphotericin B were approximately 2·3 and 1·6 mg/kg for mice and rats, respectively. The multiple dose toxicity test confirmed that AmBisome was well tolerated by both spocies. There were no deaths observed among mia receiving 25 or 50 mg/kg AmBisome for 14 days, and only two deaths among mice receiving 75 mg/kg AmBisome. One rat died in the group receiving 25 mg/kg AmBisome for 30 days. However, five of ten and nine of ten rats died in the groups treated with 50 and 75 mg/kg AmBisome, respectively. Hepatotoxicity was evident by elevation in serum liver enzyme levels for thesc groups. Initial pharmacokinetic evaluations demonstrated that peak plasma conentrations of 87 and 118 mg/kg, respectively, were attained in mice and rats after injection with 5 mg/kg AmBisome. Terminal plasma half-lives of 3·36 and 7·56 h were calculated for mice and rats, respectively.Tissue accumulations of amphotericin B resulting from multiple dose intravenous administration of either conventional amphotericin B or ArnBisome were determined. At equivalent doses of 1 mg/kg, AmBisome treatment resulted in higher liver and spleen uptake of drug, but lower kidney and lung uptake than amphotericin B.At 5 mg/kg, AmBisome treatment resulted in conantrations of drug in the kidney and lungs that were comparable to corresponding tissue levels obsevered in the group treated with 1 mg/kg conventional amphoterian B. However, liver and spleen conantrations were more than ten-fold greater relative to the group treated with 1 mg/kg conventional drug. The 5 mg/kg AmBisome treatment also resulted in a low, but measurable accumulation of amphotericin B in brain tissue. The results show that the AmBisome formulation has greatly reduced the toxicity of amphotericin B, and high plasma concentrations and tissue accumulations of drug can be achieved with non-toxic doses of AmBisome.

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