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Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer
Author(s) -
Van Sebille Ysabella Z.A.,
Gibson Rachel J.,
Wardill Hannah R.,
Ball Imogen A.,
Keefe Dorothy M.K.,
Bowen Joanne M.
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31048
Subject(s) - pharmacology , ussing chamber , diarrhea , medicine , intestinal mucosa , secretion
Dacomitinib, an irreversible small‐molecule pan‐ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats ( n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib‐induced diarrhea ( p = 0.0003), and did not attenuate weight loss ( p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti‐secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib‐induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO‐1 and occludin, and internalization of claudin‐1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib‐induced ileal damage. Crofelemer worsened dacomitinib‐induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.