Kang Jeong Yeon, Gao Jieming, Shin Dae Hwan, Alvarez Celeste, Zhong Weixiong, Kwon Glen S
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792.
Pharm Nanotechnol. 2016;4(1):16-23. doi: 10.2174/2211738504666160301233754.
Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol.
The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen.
AmB existed primarily in a monomeric state in poly(ethylene glycol)--poly(N-hexyl stearate L-aspartamide) (PEG--PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone, was highly self-aggregated based on absorption spectroscopy.
After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (V) and total systemic clearance (CL) relative to Fungizone. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone were similar to day 1. The treatment of Fungizone also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys.
In summary, mAmB has less renal toxicity than AmB as Fungizone in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB .
单体两性霉素B（AmB），即解聚后的AmB，通过利用单体AmB对麦角固醇的结合选择性高于胆固醇，已成为在膜水平降低肾毒性的主要策略。
本研究旨在表征多次给药方案后大鼠体内单体AmB的药代动力学（PK）和肾毒性。
在聚（乙二醇）-聚（N-己基硬脂酰胺-L-天冬酰胺）（PEG-PHSA）胶束中，AmB主要以单体状态存在（mAmB），摩尔比为2:1，而作为标准制剂的两性霉素B脂质体（Fungizone），根据吸收光谱显示高度自聚集。
单次静脉注射后，相对于Fungizone，mAmB显著（p<0.001）增加了血浆药物浓度-时间曲线下面积（AUC），并降低了分布容积（V）和总全身清除率（CL）。每日静脉注射剂量为1.0mg/kg，持续7天，mAmB和Fungizone的PK参数与第1天相似。Fungizone治疗还显著（p<0.05）使尿酶N-乙酰-β-D-氨基葡萄糖苷酶（NAG）和肾损伤分子-1（KIM-1）水平分别升高3.1倍和3.0倍，而mAmB组NAG和KIM-1水平未改变，这与切除肾脏的苏木精和伊红（H&E）染色结果一致。
综上所述，在多次给药方案后，大鼠体内mAmB的肾毒性低于Fungizone形式的AmB，验证了AmB的聚集状态假说。
