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  2. Immunohistochemical localization of afatinib in male rat intestines and skin after its oral administration

Immunohistochemical localization of afatinib in male rat intestines and skin after its oral administration

  • Acta Histochem. 2019 Nov;121(8):151439. doi: 10.1016/j.acthis.2019.09.001.
Yutaro Yamamoto 1 Tetsuya Saita 2 Yuta Yamamoto 1 Rintaro Sogawa 3 Sakiko Kimura 3 Yutaka Narisawa 3 Shinya Kimura 4 Masashi Shin 1
Affiliations

Affiliations

  • 1 Applied Life Science Department, Faculty of Biotechnology and Life Science, Sojo University, 4-22-1 Ikeda, Kumamoto, 860-0082, Japan.
  • 2 Applied Life Science Department, Faculty of Biotechnology and Life Science, Sojo University, 4-22-1 Ikeda, Kumamoto, 860-0082, Japan. Electronic address: sait1102@life.sojo-u.ac.jp.
  • 3 Department of Pharmacy, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
  • 4 Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.
Abstract

Afatinib, a second-generation tyrosine kinase inhibitor, was designed to bind covalently to and irreversibly inhibit active ErbB family receptors. The major metabolites of afatinib in human plasma are adducts of afatinib covalently bound to plasma proteins via. the Michael addition reaction. These findings suggest that afatinib may form covalent bonds with proteins in tissue and be localized in tissue. However, there is no method for the specific detection of afatinib-protein conjugates localized in tissue. In this paper, we aimed to develop an immunohistochemical protocol to detect afatinib-protein conjugates. Immunostainings were performed with male rat intestinal tract and skin at 24 h after an oral administration of afatinib. In the intestinal tract, strong staining was observed in the ileum and colon, but only slight staining was observed in the duodenum and jejunum. In the skin, strong staining was observed in the epidermis, sebaceous glands and hair follicles. Immunohistochemistry for afatinib-protein conjugates could be a useful tool to detect the localization of such conjugates. This study is the first to elucidate the localization of afatinib-protein conjugates in the rat intestinal tract and skin and is expected to be of great use in efforts to clarify the mechanism underlying afatinib-induced diarrhoea or skin toxicities.

Keywords

Afatinib; Immunohistochemistry; Intestine; Localization; Skin.

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