Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging

// Meiko Nishimura 1, * , Mitsuhiro Hayashi 2, 3, * , Yu Mizutani 1 , Kei Takenaka 1 , Yoshinori Imamura 1 , Naoko Chayahara 1, 4 , Masanori Toyoda 1 , Naomi Kiyota 1 , Toru Mukohara 1, 5 , Hiroaki Aikawa 3 , Yasuhiro Fujiwara 6 , Akinobu Hamada 2, 3, 7 and Hironobu Minami 1, 5 1 Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan 2 Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan 3 Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan 4 Present Address: Department of Medical Oncology, Kobe Minimally invasive Cancer Center, Kobe, Hyogo, Japan 5 Cancer Center, Kobe University Hospital, Kobe, Hyogo, Japan 6 Department of Breast and Medical Oncology, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan 7 Department of Medical Oncology and Translational Research, Graduate school of Medical Sciences, Kumamoto University, Kumamoto, Japan * These authors contributed equally to this work Correspondence to: Hironobu Minami, email: hminami@med.kobe-u.ac.jp Akinobu Hamada, email: akhamad@ncc.go.jp Keywords: erlotinib; rash; mass spectrometry imaging; drug distribution; liquid chromatography-tandem mass spectrometry Abbreviations: EGFR-TKI: epidermal growth factor receptortyrosine kinase inhibitor; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MSI: mass spectrometry imaging; MALDI: matrix-assisted laser desorption/ionization; LMD: laser microdissection Received: August 23, 2017      Accepted: March 08, 2018      Published: April 06, 2018 ABSTRACT Background: The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results: Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm 2 ; P = 0.009 in paired t -test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm 3 ; P = 0.028 in paired t -test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions: Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods: We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with laser microdissection.