Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.
Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.
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DOI：
10.1038/srep23749
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发表时间：
2016-03-30
影响因子：
4.6
通讯作者：
Hamada A
中科院分区：
文献类型：
--
作者：
Aikawa H;Hayashi M;Ryu S;Yamashita M;Ohtsuka N;Nishidate M;Fujiwara Y;Hamada A
在抗癌药物的开发中，靶组织中的药物浓度测量被认为是预测药物疗效和安全性的关键。液相色谱-串联质谱法（LC-MS/MS）常用来测定平均药物浓度；然而，空间信息在靶组织中完全丢失。质谱成像（MSI）近年来作为一种创新的工具应用于检测药物在异质靶标中的分子分布。本研究利用基质辅助激光解吸电离- msi和LC-MS/MS技术的结合，研究了新型间变性淋巴瘤激酶抑制剂alectinib的脑内传递性。我们首先分析了FVB小鼠的药代动力学特征，然后使用Mdr1a/b敲除小鼠检测了多药耐药蛋白1 （MDR1）的影响，包括alectinib在大脑中的定量分布。虽然小鼠血浆中alectinib浓度没有差异，但Mdr1a/b敲除小鼠与FVB小鼠的大脑中发现弥漫性alectinib分布。这些结果表明，除了在抗癌药物开发和转化研究的设计研究中可能使用定量MSI，还可以在微观水平上阐明药物在大脑中的分布。
In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization–MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research.