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Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging
Hiroaki Aikawa1, Mitsuhiro Hayashi1,2, Shoraku Ryu2
1Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Abstract:
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.
Insights
Quantitative mass spectrometry imaging (MSI) revealed that multidrug resistance protein-1 (MDR1) affects alectinib distribution in the brain. This technique enhances understanding of anticancer drug delivery and efficacy in translational research.
Area of Science:
- Pharmacology
- Oncology
- Analytical Chemistry
Background:
- Accurate drug concentration measurement in target tissues is vital for anticancer drug development.
- Traditional methods like LC-MS/MS provide average concentrations but lack spatial information.
- Mass spectrometry imaging (MSI) offers a novel approach to visualize molecular distribution in complex biological samples.
Purpose of the Study:
- To investigate the intra-brain distribution of alectinib, an anaplastic lymphoma kinase inhibitor.
- To evaluate the role of multidrug resistance protein-1 (MDR1) in alectinib brain penetration.
- To demonstrate the utility of quantitative MSI in drug distribution studies.
Main Methods:
- Combination of matrix-assisted laser desorption ionization-MSI and LC-MS/MS techniques.
- Pharmacokinetic analysis in FVB mice.
- Comparative analysis using Mdr1a/b knockout mice and FVB mice to assess MDR1 influence.
Main Results:
- Plasma concentrations of alectinib were similar between FVB and Mdr1a/b knockout mice.
- Alectinib exhibited diffuse distribution in the brains of Mdr1a/b knockout mice compared to FVB mice.
- Quantitative MSI successfully visualized microscopic drug distribution within the brain.
Conclusions:
- MDR1 significantly influences the brain distribution of alectinib.
- Quantitative MSI is a powerful tool for elucidating drug distribution at a microscopic level.
- This approach can aid in designing anticancer drug development and translational research studies.
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