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两性霉素 B 载药聚乙二醇-聚 N-己基硬脂酰基 L-天冬酰胺胶束的药代动力学和肾毒性

Pharmacokinetics and nephrotoxicity of amphotericin B-incorporated poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) micelles.

机构信息

Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.

出版信息

J Pharm Sci. 2011 Jun;100(6):2064-70. doi: 10.1002/jps.22445. Epub 2010 Dec 23.

DOI:10.1002/jps.22445
PMID:21491436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4420017/
Abstract

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.

摘要

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。

相似文献

[1]
Pharmacokinetics and nephrotoxicity of amphotericin B-incorporated poly(ethylene glycol)-block-poly(N-hexyl stearate l-aspartamide) micelles.

J Pharm Sci. 2010-12-23

[2]
Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen.

Pharm Nanotechnol. 2016

[3]
The effect of fatty acid substitution on the in vitro release of amphotericin B from micelles composed of poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide).

J Control Release. 2002-2-19

[4]
Micelles self-assembled from poly(ethylene oxide)-block-poly(N-hexyl stearate L-aspartamide) by a solvent evaporation method: effect on the solubilization and haemolytic activity of amphotericin B.

J Control Release. 2001-11-9

[5]
Enhanced stability of PEG-block-poly(N-hexyl stearate l-aspartamide) micelles in the presence of serum proteins.

Mol Pharm. 2010-8-2

[6]
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[7]
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[8]
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[9]
Mixed micellar nanoparticle of amphotericin B and poly styrene-block-poly ethylene oxide reduces nephrotoxicity but retains antifungal activity.

Arch Pharm Res. 2007-10

[10]
Relative aggregation state and hemolytic activity of amphotericin B encapsulated by poly(ethylene oxide)-block-poly(N-hexyl-L-aspartamide)-acyl conjugate micelles: effects of acyl chain length.

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引用本文的文献

[1]
Phospholipid-Conjugated PEG--PCL Copolymers as Precursors of Micellar Vehicles for Amphotericin B.

Polymers (Basel). 2021-5-27

[2]
Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol.

Pharmaceutics. 2020-2-25

[3]
Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation.

Pharm Res. 2017-5

[4]
Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen.

Pharm Nanotechnol. 2016

[5]
Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B.

Pharm Res. 2016-9

本文引用的文献

[1]
The effects of Bile Acids on Freshly Isolated Rat Glomeruli and Proximal Tubular Fragments.

Toxicol In Vitro. 1997-1-10

[2]
Enhanced stability of PEG-block-poly(N-hexyl stearate l-aspartamide) micelles in the presence of serum proteins.

Mol Pharm. 2010-8-2

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Hum Exp Toxicol. 2009-5

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