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Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido\u2010pyrrolooxazinedione (R)\u2010BPO\u201027 inhibits CFTR chloride conductance with low\u2010nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)\u2010BPO\u201027 for treatment of secretory diarrheas caused by cholera and\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    enterotoxins. (R)\u2010BPO\u201027 fully blocked CFTR chloride conductance in epithelial cell cultures and intestine after cAMP agonists, cholera toxin, or heat\u2010stable enterotoxin of\n                    <jats:italic>E. coli<\/jats:italic>\n                    (STa toxin), with IC50 down to ~5 nM. (R)\u2010BPO\u201027 prevented cholera toxin and STa toxin\u2010induced fluid accumulation in small intestinal loops, with IC50 down to 0.1 \u03bcg\/kg. (R)\u2010BPO\u201027 did not impair intestinal fluid absorption or inhibit other major intestinal transporters. Pharmacokinetics in mice showed &gt;90% oral bioavailability with sustained therapeutic serum levels for &gt;4 h without the significant toxicity seen with 7\u2010d administration at 5 \u03bcg\/kg\/d. As evidence to support efficacy in human diarrheas, (R)\u2010BPO\u201027 blocked fluid secretion in primary cultures of enteroids from human small intestine and anion current in enteroid monolayers. These studies support the potential utility of (R)\u2010BPO\u201027 for therapy of CFTR\u2010mediated secretory diarrheas.\u2014Cil, O., Phuan, P.\u2010W., Gillespie, A.M., Lee, S., Tradtrantip, L., Yin, J., Tse, M., Zachos, N.C., Lin, R., Donowitz, M., Verkman, A.S. Benzopyrimido\u2010pyrrolo\u2010oxazine\u2010dione CFTR inhibitor (R)\u2010BPO\u201027 for antisecretory therapy of diarrheas caused by bacterial enterotoxins. FASEB J. 31, 751\u2013760 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">http:\/\/www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201600891r","type":"journal-article","created":{"date-parts":[[2016,11,9]],"date-time":"2016-11-09T08:18:56Z","timestamp":1478679536000},"page":"751-760","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Benzopyrimido\u2010pyrrolo\u2010oxazine\u2010dione CFTR inhibitor (R)\u2010BPO\u201027 for antisecretory therapy of diarrheas caused by bacterial enterotoxins"],"prefix":"10.1096","volume":"31","author":[{"given":"Onur","family":"Cil","sequence":"first","affiliation":[{"name":"Department of Medicine University of California San Francisco San Francisco California USA"},{"name":"Department of Physiology University of California San Francisco San Francisco California 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