Invited reviewDrug-induced secretory diarrhea: A role for CFTR
Graphical abstract
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.