Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.
J Pharm Sci. 2011 Jun;100(6):2064-70. doi: 10.1002/jps.22445. Epub 2010 Dec 23.
The purpose of this investigation was to study the pharmacokinetics and nephrotoxicity of amphotericin B (AmB), incorporated in poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) (PEG-b-PHSA) micelles (AmB/PEG-b-PHSA). After AmB/PEG-b-PHSA or AmB for injection, United States Pharmacopeia (USP), was dosed intravenously in rats (0.8 mg/kg), serum was collected over 72 h, and organs collected at 72 h for AmB analysis. To test for the nephrotoxicity caused by AmB, renal markers of damage were assessed 24 h after a single injection of AmB/PEG-b-PHSA or AmB for injection, USP, focusing on detection of urinary enzymes. PEG-b-PHSA micelles caused a significantly lower area under serum concentration curve and higher clearance relative to AmB for injection, USP. PEG-b-PHSA micelles lowered the distribution of AmB in liver and lung tissues, but did not significantly lower the level of AmB in the kidneys relative to AmB for injection, USP. However, urine levels of N-acetyl-β-glucosaminidase and γ-glutamyltransferase were significantly lower for AmB/PEG-b-PHSA relative to AmB for injection, USP. In summary, PEG-b-PHSA micelles reduced the nephrotoxicity of AmB, the dose-limiting toxicity of this important antifungal agent.
本研究旨在研究两性霉素 B（AmB）在聚乙二醇-聚（N-己基硬脂酰胺 L-天冬酰胺）（PEG-b-PHSA）胶束（AmB/PEG-b-PHSA）中的药代动力学和肾毒性。AmB/PEG-b-PHSA 或 AmB 注射液经静脉注射给药后（0.8mg/kg），在 72 小时内收集血清，并在 72 小时内收集器官进行 AmB 分析。为了测试 AmB 引起的肾毒性，在单次注射 AmB/PEG-b-PHSA 或 AmB 注射液后 24 小时，评估了肾损伤标志物，重点检测尿液酶。与 AmB 注射液相比，PEG-b-PHSA 胶束导致血清浓度曲线下面积显著降低，清除率增加。PEG-b-PHSA 胶束降低了 AmB 在肝和肺组织中的分布，但与 AmB 注射液相比，对肾脏中 AmB 的水平无显著降低。然而，AmB/PEG-b-PHSA 的尿液 N-乙酰-β-氨基葡萄糖苷酶和γ-谷氨酰转移酶水平显著低于 AmB 注射液。总之，PEG-b-PHSA 胶束降低了两性霉素 B 的肾毒性，两性霉素 B 是一种重要的抗真菌药物，其毒性限制了其应用。
