Drug-induced secretory diarrhea: A role for CFTR

• Published in: Pharmacological research 2015-12, Vol.102, p.107-112
• Main Authors: Moon, Changsuk, Zhang, Weiqiang, Sundaram, Nambirajan, Yarlagadda, Sunitha, Reddy, Vadde Sudhakar, Arora, Kavisha, Helmrath, Michael A., Naren, Anjaparavanda P.
• Format: Article
• Language: English
• Subjects: Animals; Cell Membrane - drug effects; Cell Membrane - metabolism; CFTR chloride channel; CFTR inhibitor; CFTR-containing macromolecular complex; Cyclic AMP - metabolism; Cyclic GMP - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Diarrhea - chemically induced; Diarrhea - metabolism; Drug-induced diarrhea; Drug-Related Side Effects and Adverse Reactions - metabolism; Humans; Intestinal fluid secretion
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2015.08.024

[Display omitted] Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein–protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea.