Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer
作者： Ysabella Z.A. Van Sebille , Rachel J. Gibson , Hannah R. Wardill , Imogen A. Ball , Dorothy M.K. Keefe
DOI: 10.1002/IJC.31048
关键词: Pharmacology 、 Crofelemer 、 Occludin 、 Chemistry 、 Chloride secretion 、 Dacomitinib 、 Tight junction 、 Ileum 、 Diarrhea 、 Mucositis
摘要: Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which been suggested to be due chloride secretory mechanisms. Based on this hypothesis, crofelemer, antisecretory agent may effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in secretion cells dacomitinib. Albino Wistar rats (n = 48) 7.5 mg/kg and/or 25 crofelemer via oral gavage 21 days. significantly worsened dacomitinib-induced diarrhea (p = 0.0003), did not attenuate weight loss (p < 0.0001). Sections the ileum colon chambers, processes analyzed. This indicated that lost its anti-secretory action presence model. Mass spectrometry revealed change serum concentration Serum FITC dextran levels was unable barrier dysfunction. Tight junction proteins visualized immunofluorescence. Qualitative analysis showed induced proteolysis ZO-1 occludin, internalization claudin-1, by crofelemer. Detailed histopathological ileal damage. suggesting drug therapy ineffective setting.
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