| Convective washout reduces the antidiarrheal efficacy of enterocyte surface-targeted antisecretory drugs. | |
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MedLine Citation:
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PMID: 23359285 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Secretory diarrheas such as cholera are a major cause of morbidity and mortality in developing countries. We previously introduced the concept of antisecretory therapy for diarrhea using chloride channel inhibitors targeting the cystic fibrosis transmembrane conductance regulator channel pore on the extracellular surface of enterocytes. However, a concern with this strategy is that rapid fluid secretion could cause convective drug washout that would limit the efficacy of extracellularly targeted inhibitors. Here, we developed a convection-diffusion model of washout in an anatomically accurate three-dimensional model of human intestine comprising cylindrical crypts and villi secreting fluid into a central lumen. Input parameters included initial lumen flow and inhibitor concentration, inhibitor dissociation constant (K(d)), crypt/villus secretion, and inhibitor diffusion. We modeled both membrane-impermeant and permeable inhibitors. The model predicted greatly reduced inhibitor efficacy for high crypt fluid secretion as occurs in cholera. We conclude that the antisecretory efficacy of an orally administered membrane-impermeant, surface-targeted inhibitor requires both (a) high inhibitor affinity (low nanomolar K(d)) to obtain sufficiently high luminal inhibitor concentration (>100-fold K(d)), and (b) sustained high luminal inhibitor concentration or slow inhibitor dissociation compared with oral administration frequency. Efficacy of a surface-targeted permeable inhibitor delivered from the blood requires high inhibitor permeability and blood concentration (relative to K(d)). |
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Authors:
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Byung-Ju Jin; Jay R Thiagarajah; A S Verkman |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The Journal of general physiology Volume: 141 ISSN: 1540-7748 ISO Abbreviation: J. Gen. Physiol. Publication Date: 2013 Feb |
Date Detail:
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Created Date: 2013-01-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985110R Medline TA: J Gen Physiol Country: United States |
Other Details:
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Languages: eng Pagination: 261-72 Citation Subset: IM |
Affiliation:
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Department of Medicine and 2 Department of Physiology, University of California, San Francisco, San Francisco, CA 94143. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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