{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:21:32Z","timestamp":1775910092499,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T00:00:00Z","timestamp":1560124800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1160955"],"award-info":[{"award-number":["OPP1160955"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013986","name":"Government of the United Kingdom","doi-asserted-by":"publisher","award":["DFI.1850-02-01291794-SUB"],"award-info":[{"award-number":["DFI.1850-02-01291794-SUB"]}],"id":[{"id":"10.13039\/100013986","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI089441"],"award-info":[{"award-number":["R01AI089441"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI111341"],"award-info":[{"award-number":["R01AI111341"]}]},{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01HD080670"],"award-info":[{"award-number":["R01HD080670"]}]},{"name":"US Department of Agriculture National Institute of Food and Agriculture","award":["2014-06183"],"award-info":[{"award-number":["2014-06183"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recent studies have illustrated the burden Cryptosporidium infection places on the lives of malnourished children and immunocompromised individuals. Treatment options remain limited, and efforts to develop a new therapeutic are currently underway. However, there are unresolved questions about the ideal pharmacokinetic characteristics of new anti-Cryptosporidium therapeutics. Specifically, should drug developers optimize therapeutics and formulations to increase drug exposure in the gastrointestinal lumen, enterocytes, or systemic circulation? Furthermore, how should researchers interpret data suggesting their therapeutic is a drug efflux transporter substrate? In vivo drug transporter\u2013mediated alterations in efficacy are well recognized in multiple disease areas, but the impact of intestinal transporters on therapeutic efficacy against enteric diseases has not been established. Using multiple in vitro models and a mouse model of Cryptosporidium infection, we characterized the effect of P-glycoprotein efflux on bumped kinase inhibitor pharmacokinetics and efficacy. Our results demonstrated P-glycoprotein decreases bumped kinase inhibitor enterocyte exposure, resulting in reduced in vivo efficacy against Cryptosporidium. Furthermore, a hollow fiber model of Cryptosporidium infection replicated the in vivo impact of P-glycoprotein on anti-Cryptosporidium efficacy. In conclusion, when optimizing drug candidates targeting the gastrointestinal epithelium or gastrointestinal epithelial infections, drug developers should consider the adverse impact of active efflux transporters on efficacy.<\/jats:p>","DOI":"10.1093\/infdis\/jiz269","type":"journal-article","created":{"date-parts":[[2019,5,18]],"date-time":"2019-05-18T07:08:05Z","timestamp":1558163285000},"page":"1188-1198","source":"Crossref","is-referenced-by-count":10,"title":["P-Glycoprotein\u2013Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium"],"prefix":"10.1093","volume":"220","author":[{"given":"Samuel L M","family":"Arnold","sequence":"first","affiliation":[{"name":"Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle"},{"name":"Center for Emerging and Reemerging Infectious Disease, University of Washington, 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University of Washington, Seattle"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly C","family":"Mccloskey","sequence":"additional","affiliation":[{"name":"Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle"},{"name":"Center for Emerging and Reemerging Infectious Disease, University of Washington, Seattle"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlie S","family":"Dorr","sequence":"additional","affiliation":[{"name":"Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle"},{"name":"Center for Emerging and Reemerging Infectious Disease, University of Washington, Seattle"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama S R","family":"Vidadala","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington, Seattle"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansi","family":"Khatod","sequence":"additional","affiliation":[{"name":"Pace University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Morada","sequence":"additional","affiliation":[{"name":"Pace University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn K","family":"Barrett","sequence":"additional","affiliation":[{"name":"Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle"},{"name":"Center for Emerging and Reemerging Infectious Disease, University of Washington, Seattle"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin J","family":"Maly","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington, Seattle"},{"name":"Department of Biochemistry, University of Washington, 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