title: Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.
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.
authors.affiliation: Division 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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Aikawa
authors.affiliation: Division 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.|Department of Molecular Imaging and Pharmacokinetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Molecular Imaging and Pharmacokinetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Shoraku
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Molecular Imaging and Pharmacokinetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Shimadzu Techno-Research Inc., 3-19-2, Minamirokugo, Ohta-ku, Tokyo 144-0045, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ohtsuka
authors.affiliation: Department of Molecular Imaging and Pharmacokinetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.|Translational Clinical Research Science &Strategy Dept., Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.|Department of Medical Oncology and Translational Research, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nishidate
authors.affiliation: Strategic Planning Bureau, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Division 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.|Department of Molecular Imaging and Pharmacokinetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.|Department of Medical Oncology and Translational Research, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D018345:Mice, Knockout; D059906:Neuroimaging; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D010880:Piperidines; C582670:alectinib