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Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging

机译:使用定量质谱成像可视化艾乐替尼在鼠脑中的空间分布

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摘要

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.
机译:在抗癌药物的开发中,目标组织中的药物浓度测量被认为对于预测药物功效和安全性至关重要。液相色谱-串联质谱法(LC-MS / MS)通常用于确定平均药物浓度。但是,目标组织中的空间信息完全丢失。质谱成像(MSI)最近已被用作检测异类靶标中药理剂分子分布的创新工具。这项研究使用基质辅助激光解吸电离– MSI和LC-MS / MS技术,研究了一种新型的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基因敲除小鼠检查了多药耐药蛋白1(MDR1)的作用,其中包括脑中alectinib的定量分布。虽然在小鼠之间血浆艾乐替尼浓度没有差异,但与FVB小鼠相比,Mdr1a / b基因敲除小鼠的大脑中弥漫性艾乐替尼分布存在。这些结果表明使用定量MSI在微观水平上澄清大脑中药物分布的潜力,并暗示可能在设计抗癌药物开发和转化研究的研究中使用。

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