Elsevier

Pharmacological Research

Volume 102, December 2015, Pages 107-112
Pharmacological Research

Invited review
Drug-induced secretory diarrhea: A role for CFTR

https://doi.org/10.1016/j.phrs.2015.08.024Get rights and content

Abstract

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.

Introduction

Diarrhea is a common side effect for many medications and accounts for approximately 7% of all drug-induced adverse effects, with over 700 drugs indicated to cause diarrhea [1], [2], [3]. Drugs including laxatives, antacids and heartburn medications, antibiotics, chemotherapy medication, anti-inflammatories as well as many supplements frequently cause diarrhea [4], [5], [6]. Drug-induced diarrhea can be acute or chronic, the severity of which is dictated by drug dosage and duration and frequency of administration [7]. In addition to causing dehydration, electrolyte imbalance, renal insufficiency, and immune dysfunction, drug-induced diarrhea decreases the efficiency of therapeutic interventions. Currently, standard approaches to mitigate a diarrheal side effect include dose reductions, treatment delays, discontinuation of therapy, and rehydration [8]. These approaches may temporarily relieve the diarrhea; however, they do not resolve the ‘root cause’ nor benefit the efficiency of ongoing therapeutic interventions.

Drugs can induce different types of diarrheas, including osmotic diarrhea, secretory diarrhea, inflammatory diarrhea, exudative diarrhea, fatty diarrhea, and motility diarrhea [1], [9]. For this review, we focus on the current understanding of drug-induced secretory diarrhea, particularly the molecular mechanisms underlying secretory diarrhea pathogenesis and the role of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in this process. Identification of a treatable target will facilitate the development of therapies that not only mitigate drug-induced diarrheal side effects, but increase the efficiency of the drug being used.

Section snippets

The domain structure of CFTR and channel regulation

CFTR is a member of the ATP-binding cassette (ABC) transporter superfamily and has two repeated membrane-spanning domains (MSD). Each of these domains contains six helices and is associated with a cytoplasmic nucleotide-binding domain (NBD) that can bind and hydrolyze ATP. Two halves of CFTR are linked by a cytoplasmic regulatory domain (R-domain) that has several consensus phosphorylation sites. N-linked glycosylation sites are located on the extracellular loop between the 7th and 8th

Drug as substrate/inhibitor of MRP4

Like CFTR, MRP4 is a member of the ABC superfamily of transporters, and it plays an important role in transporting a wide variety of endogenous and xenobiotic organic anionic compounds out of cells [26]. Some of the endogenous substrates of MRP4 play important roles in cellular communication and signaling, including cAMP, cGMP, ADP, eicosanoids, bile acids, urate, and conjugated steroid hormones [27]. MRP4 is critical for the absorption, disposition, or excretion of targeted drugs, including

Perspective: inhibition of CFTR for the management of drug-induced secretory diarrhea

Compelling evidence suggests a role for CFTR in the pathogenic process of drug-induced secretory diarrhea. Since CFTR is a validated drug target for cystic fibrosis therapy and combating enterotoxin-induced secretory diarrhea, inhibition of CFTR channel function is a potentially viable approach to management of drug-induced secretory diarrhea [42], [43]. Several potent small-molecule CFTR inhibitors with improved pharmacokinetics properties have been discovered, including BPO-27 and iOWH032 [44]

Conclusion

Diarrhea is a common adverse effect of drug medications that can be elicited through different pathophysiological mechanisms. For drug-induced secretory diarrhea, particularly for drugs that perturb the intracellular secondary messenger signaling, compelling evidence suggests a role for CFTR in the pathogenic process. Since CFTR is a validated therapeutic target for cystic fibrosis and a target for other types of secretory diarrhea, inhibition of CFTR channel function represents a potential

Contributors

C. Moon and W. Zhang contributed equally to this paper. All authors participated in critical review of the manuscript, and have approved the final version.

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

The authors thank J. Denise Wetzel, CCHMC Medical Writer, for review and editing of the manuscript. This work was supported by the U.S. National Institutes of Health grants R01-DK080834 and R01-DK093045 to A. P. Naren, R01HL123535 to W. Zhang.

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    Both authors contributed equally to this work.

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