A unilamellar liposomal formulation of amphotericin B (LAmB) known as AmBisome was safely administered intravenously to 20 rabbits at 0.5, 1.0, 2.5, 5, or 10 mg/kg of body weight, whereas of 12 rabbits given desoxycholate amphotericin B (DAmB) intravenously at 0.5, 1.0, or 1.5 mg/kg, 2 died of acute cardiac toxicity when DAmB was administered at the highest dose. Single-dose LAmB (1 mg/kg) achieved a maximum concentration in serum (Cmax) of 26 ± 2.4 ,ug/ml and an area under the curve to infinity (AUC O) of 60 ± 16 ,ug h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower Cmax (4.7 ± 0.2 -ug/ml; P = 0.001) and a lower AUC -,, (30.6 ± 2.2 ,ug * h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher Cmax (287 ± 14 ,ug/ml) and AUC0_Q (2,223 ± 246 ,ug* h/ml) occurred, indicating saturable elimination. After chronic dosing (n = 4) with LAmB at 5.0 mg/kg/day for 28 days or DAmB at 1.0 mg/kg/day for 28 days, LAmB achieved daily peak levels of 122.8 ± 5.8 ,ug/ml and trough levels of 34.9 ± 1.8 ,ug/ml, while DAmB reached a peak of only 1.76 ± 0.11 ,ig/ml and a trough of 0.46 ± 0.04 ,ig/ml (P . 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 ± 39 ,ug/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 ± 6 ,ug/g after DAmB dosing (1 mg/kg/day) (P = 0.002). Accumulation in kidneys, however, remained 14-fold lower (P = 0.04) following LAmB dosing (0.87 ± 0.61 j,g/g) than after DAmB dosing (12.7 + 4.6 ,ug/g). Nephrotoxicity occurred in only one of four LAmB-treated animals, while it occurred in all four chronically DAmB-treated animals; mild hepatotoxicity with transaminase elevations was seen in one MATERUILS AND METHODS Drugs. LAmB was provided as a lyophilized yellow powder (AmBisome) by Vestar, Inc. The drug's constituents are 53.3% hydrogenated soy phosphatidylcholine, 13.1% cholesterol, 21.1% distearoylphosphatidylglycerol, and 12.5% amphotericin B (by weight, or at a molar ratio of 2:1:0.8:0.4, respectively). The powder was initially reconstituted with sterile water to an initial concentration of 2 mg/ml, and the solution was then heated to 60°C for 10 min to ensure dissolution. The solution was then filtered through a 5-,um-pore-size filter to remove any aggregates that might remain and was diluted to a final concentration of 0.5 mg/ml with 5% glucose in water. DAmB was prepared from commercially available Fungizone (BristolMyers Squibb, Princeton, N.J.) by dissolving the initial powder with sterile water and then further diluting the solution with 5% glucose in water to a final concentration of 1 mg/ml.Rabbits. Female New Zealand White rabbits weighing between 2.5 and 3.0 kg were used for the study. Animals were housed individually and were provided food and water ad libitum. While the rabbits were under general anesthesia, a silastic central venous catheter was surgically placed in each rabbit for repeated, nontraumatic venous access as...