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A procedure for method development and protein binding ratio as the indicator of sensitivity with anticancer agents
Yoshiharu Hayashi1, Mayu Ohuchi2, Shoraku Ryu3
1Division of Molecular Pharmacology, 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 and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan; Bioanalysis Research Department, CMIC Pharma Science Co., Ltd., 17-18 Nakahata-cho,Nishiwaki, Hyogo, 677-0032, Japan.
Abstract:
The concentration and distribution of a drug and its metabolites in tissues are key factors for elucidating both drug efficacy and toxicity in drug development. In this study we developed a pharamaco-imaging procedure for 12 agents and investigated the relationship between the properties of target compounds and the sensitivities of detection in matrix-assisted laser desorption/ionization-mass spectrometer imaging (MALDI-MSI). We prepared mock samples with mouse liver homogenates diluted with gelatin solution, limit of detection concentrations of each compound was confirmed. The correlation was evaluated between the intensities of mass signals obtained in MALDI-MSI with each test compound (the intensities of the test compounds) at a consistent concentration and the properties of each test compound. The liver homogenate diluted with gelatin solution showed easier handling and lower coefficients of variation than did liver homogenate only, and can be used as a good surrogate matrix. Based on the analysis of 12 agents, the protein binding ratios showed significant correlation to the detection sensitivities. We presented a procedure for standardization of pharmaco-imaging method development with an in-tissue method using MALDI-MS. Our results indicated the correlation between test compound's sensitivity and their protein binding ratios in plasma or serum.