{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T22:13:53Z","timestamp":1768688033034,"version":"3.49.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["1R21DA035751"],"award-info":[{"award-number":["1R21DA035751"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dan L Duncan Comprehensive Cancer Center","award":["P30 CA125123"],"award-info":[{"award-number":["P30 CA125123"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neratinib is a pan-HER tyrosine kinase inhibitor newly approved by FDA in 2017 to treat HER2-positive breast cancer, but the phase III trial of neratinib showed that 96% of the patients taking neratinib experienced diarrhea. So far very few mechanistic studies explore neratinib-induced gastrointestinal (GI) toxicity. Hereby, we performed toxicity studies in mice to characterize the potential mechanism underlying this adverse effect. C57BL\/6\u00a0J mice were separated into three groups A, B, C. Group A received vehicle; group B was orally dosed with 100\u00a0mg\/kg neratinib once daily for 18\u00a0days. Group C was dosed with 100\u00a0mg\/kg neratinib for 12\u00a0days and switched to vehicle for 6\u00a0days. Intestine and liver were collected for further analysis. Human intestine-derived cells were treated with neratinib in vitro. Our results showed that 12\u00a0days treatment of neratinib caused persistent histological damage in mouse GI tract. Both gene expression and activity of Cyp3a11, the major enzyme metabolizing neratinib in mice was reduced in small intestine. The gene expression of proinflammatory cytokines increased throughout the GI tract. Such damages were not recovered after 6\u00a0days without neratinib treatment. In addition, in vitro data showed that neratinib was potent in killing human intestine-derived cell lines. Based on such findings, we hypothesized that neratinib downregulates intestinal CYP3A enzyme to cause excessive drug disposition, eventually leading to gut injury.<\/jats:p>","DOI":"10.1093\/toxres\/tfab111","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T04:09:15Z","timestamp":1635826155000},"page":"184-194","source":"Crossref","is-referenced-by-count":13,"title":["Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5799-3539","authenticated-orcid":false,"given":"Gabriel","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Dagher","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romi","family":"Ghose","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"2022022804495568100_ref1","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1158\/1078-0432.CCR-17-3628","article-title":"U.S. food and drug administration approval: neratinib for the extended adjuvant treatment of early-stage HER2-positive breast cancer","volume":"24","author":"Singh","year":"2018","journal-title":"Clin Cancer 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management","volume":"10","author":"Tao","year":"2021","journal-title":"Toxicol Res (Camb)"},{"key":"2022022804495568100_ref5","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.126444","article-title":"Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea","volume":"4","author":"Duan","year":"2019","journal-title":"JCI Insight"},{"key":"2022022804495568100_ref6","doi-asserted-by":"crossref","first-page":"e14490","DOI":"10.14814\/phy2.14490","article-title":"Potentiation of calcium-activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor-induced diarrhea","volume":"8","author":"Kim","year":"2020","journal-title":"Physiol Rep"},{"key":"2022022804495568100_ref7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/ijc.31048","article-title":"Dacomitinib-induced diarrhea: targeting chloride secretion with crofelemer","volume":"142","author":"Van","year":"2018","journal-title":"Int J Cancer"},{"key":"2022022804495568100_ref8","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1002\/ijc.30699","article-title":"Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats","volume":"140","author":"Van","year":"2017","journal-title":"Int J Cancer"},{"key":"2022022804495568100_ref9","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00280-018-3756-8","article-title":"Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model","volume":"83","author":"Secombe","year":"2019","journal-title":"Cancer Chemother Pharmacol"},{"key":"2022022804495568100_ref10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12282-020-01133-9","article-title":"Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant","volume":"28","author":"Secombe","year":"2021","journal-title":"Breast Cancer"},{"key":"2022022804495568100_ref11","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.annonc.2020.05.012","article-title":"Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial","volume":"31","author":"Barcenas","year":"2020","journal-title":"Ann Oncol"},{"key":"2022022804495568100_ref12","doi-asserted-by":"crossref","first-page":"e4272","DOI":"10.1002\/bmc.4272","article-title":"Metabolic profiles of neratinib in rat by using ultra-high-performance liquid chromatography coupled with diode array detector and Q-Exactive Orbitrap tandem mass spectrometry","volume":"32","author":"Liu","year":"2018","journal-title":"Biomed Chromatogr"},{"key":"2022022804495568100_ref13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/j.1365-2125.2010.03845.x","article-title":"Pharmacokinetics of oral neratinib during 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