TOXICOLOGICAL PROFILE AND PHARMACOKINETICS OF A UNILAMELLAR LIPOSOMALVESICLE FORMULATION OF AMPHOTERICIN-B IN RATS

AmBisome (ABLP) is a unilamellar liposomal preparation of amphotericin B that has demonstrated an improved safety profile compared to conven tional amphotericin B. Single-and multiple-dose pharmacokinetics were determined by using noncompartmental methods for rats administered ABL P at 1, 3, 9, and 20 mg/kg/day. The toxicological profile was evaluate d following 30 consecutive days of intravenous ABLP administration. Me an plasma amphotericin B concentrations reached 500 and 380 mu g/ml (m ales and females, respectively) following 30 days of ABLP administrati on at 20 mg/kg. The overall apparent half-life was 11.2 +/- 4.5 h (mal es) or 8.7 +/- 2.2 h (females), and the overall clearance (CL) was 9.4 +/- 5.5 ml/h/kg (males) or 10.2 +/- 4.1 m/h/kg (females), ABLP appear s to undergo saturable disposition, resulting in a non-dose-proportion al amphotericin B area under the curve and a lower CL at higher doses. Histopathological examination revealed dose-related transitional-cell hyperplasia in the transitional epithelium of the urinary tract (kidn ey, ureters, and urinary bladder) and moderate hepatocellular necrosis at the 20-mg/kg/day dose, Administration of ABLP in doses of up to 20 mg/kg/day resulted in 100-fold higher plasma amphotericin B concentra tions, with significantly lower toxicity than that reported with conve ntional amphotericin B therapy.