Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds
Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds
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DOI：
10.1002/jps.24575
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发表时间：
2016-02-01
影响因子：
3.8
通讯作者：
Friden, Markus
中科院分区：
文献类型：
--
作者：
Backstrom, Erica;Lundqvist, Anders;Friden, Markus
确定吸入后肺部靶点的游离药物浓度的挑战限制了通过化合物设计优化靶点暴露的可能性。在这项研究中，发展了一种新的大鼠肺切片方法学，并应用于研究肺组织的药物摄取及其发生机制。新鲜制备的大鼠肺切片(500 Mm)与药物孵育后，测定肺内游离药物的分布体积(V-u，V-肺)，即切片中药物的总浓度除以缓冲液(非结合)浓度。一组吸入药物化合物的V-U，V-肺测定范围从沙丁胺醇的2.21毫升/克到二碱类化合物A的2970毫升/克。与溶酶体pH调节剂莫能菌素共同孵育，可使组织对碱性心得安的摄取抑制13%，表明溶酶体被广泛捕获。阳离子MPP+和二碱化合物A的细胞分配率特别高，可能是因为载体介导的运输和溶酶体捕获。结果表明，不同的因素对组织摄取是重要的，所提出的方法可以用于吸入性化合物的轮廓分析，从而更好地了解药物在肺部的分布和暴露。(C)2016年美国药剂师协会(R)。爱思唯尔公司出版，版权所有。
The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 mm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (V-u,V-lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. V-u,V-lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.