Lee J W, Amantea M A, Francis P A, Navarro E E, Bacher J, Pizzo P A, Walsh T J
Infectious Diseases Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Antimicrob Agents Chemother. 1994 Apr;38(4):713-8. doi: 10.1128/AAC.38.4.713.
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 micrograms/ml and an area under the curve to infinity (AUC0-infinity) of 60 +/- 16 micrograms.h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower Cmax (4.7 +/- 0.2 micrograms/ml; P = 0.001) and a lower AUC0-infinity (30.6 +/- 2.2 micrograms.h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher Cmax (287 +/- 14 micrograms/ml) and AUC0-infinity (2,223 +/- 246 micrograms.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 micrograms/ml and trough levels of 34.9 +/- 1.8 micrograms/ml, while DAmB reached a peak of only 1.76 +/- 0.11 microgram/ml and a trough of 0.46 +/- 0.04 microgram/ml (P < or = 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 +/- 39 micrograms/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 +/- 6 micrograms/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 microgram/g) than after DAmB dosing (12.7 +/- 4.6 microgram/g). Nephrotoxicity occurred in only one of four LAmB treated animals, while it occurred in all four chronically DAmB-treated animals: mild hepatozicity with transaminase elevations was seen in one LAmB-treated rabbit. We conclude that LAmB safely achieved higher Cmax(s) and AUC0-infinity(s) and demonstrated saturable, nonlinear elimination from plasma via reticuloendothelial organ uptake. Take reduced nephrotoxicity of LAmB correlated with diminished levels of amphotericin B in the kidneys.
一种名为安必素（AmBisome）的两性霉素B单室脂质体制剂，以0.5、1.0、2.5、5或10mg/kg体重的剂量静脉注射给20只兔子，给药过程安全；而12只兔子静脉注射去氧胆酸盐两性霉素B（DAmB），剂量为0.5、1.0或1.5mg/kg，当给予最高剂量的DAmB时，有2只兔子死于急性心脏毒性。单剂量的安必素（1mg/kg）在血清中达到的最大浓度（Cmax）为26±2.4μg/ml，曲线下面积至无穷大（AUC0-∞）为60±16μg·h/ml，相比之下，单剂量的DAmB（1.0mg/kg）达到的Cmax较低（4.7±0.2μg/ml；P = 0.001），AUC0-∞也较低（30.6±2.2μg·h/ml；P = 0.07）。给予单剂量的安必素（10mg/kg）后，出现了不成比例的更高的Cmax（287±14μg/ml）和AUC0-∞（2223±246μg·h/ml），表明存在饱和消除。在以5.0mg/kg/天的剂量对4只兔子进行28天的安必素慢性给药或1.0mg/kg/天的剂量对4只兔子进行28天的DAmB慢性给药后，安必素的每日峰值水平为122.8±5.8μg/ml，谷值水平为34.9±1.8μg/ml，而DAmB的峰值仅为1.76±0.11μg/ml，谷值为0.46±0.04μg/ml（P≤0.001）。观察到两性霉素B在网状内皮器官中有显著蓄积，安必素慢性给药（5mg/kg/天）后肝脏中的含量为239±39μg/g，比DAmB给药（1mg/kg/天）后的33±6μg/g高7倍（P = 0.002）。然而，安必素给药后（0.87±0.61μg/g）肾脏中的蓄积比DAmB给药后（12.7±4.6μg/g）低14倍（P = 0.04）。在接受安必素治疗的4只动物中只有1只发生了肾毒性，而在所有4只接受DAmB慢性治疗的动物中均发生了肾毒性：在1只接受安必素治疗的兔子中观察到伴有转氨酶升高的轻度肝毒性。我们得出结论，安必素安全地达到了更高的Cmax和AUC0-∞，并通过网状内皮器官摄取显示出从血浆中的饱和、非线性消除。安必素肾毒性降低与肾脏中两性霉素B水平降低相关。
