{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:24:47Z","timestamp":1779927887222,"version":"3.53.1"},"reference-count":29,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:p>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\u2013diffusion 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 (Kd), 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 Kd) to obtain sufficiently high luminal inhibitor concentration (&amp;gt;100-fold Kd), 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 Kd).<\/jats:p>","DOI":"10.1085\/jgp.201210885","type":"journal-article","created":{"date-parts":[[2013,1,28]],"date-time":"2013-01-28T16:52:21Z","timestamp":1359391941000},"page":"261-272","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Convective washout reduces the antidiarrheal efficacy of enterocyte surface\u2013targeted antisecretory drugs"],"prefix":"10.1085","volume":"141","author":[{"given":"Byung-Ju","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"},{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay R.","family":"Thiagarajah","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"},{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"},{"name":"Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.S.","family":"Verkman","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"},{"name":"Department of Medicine 1 and 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 94143 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,1,28]]},"reference":[{"key":"2023072622390254100_bib1","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1172\/JCI0217301","article-title":"Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors","volume":"110","author":"Al-Awqati","year":"2002","journal-title":"J. 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