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However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug\u2013drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug\u2013drug interactions with itraconazole.<\/jats:p>","DOI":"10.3390\/molecules27206815","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T05:31:18Z","timestamp":1665552678000},"page":"6815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B"],"prefix":"10.3390","volume":"27","author":[{"given":"Dominique A.","family":"Garrison","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4124-3362","authenticated-orcid":false,"given":"Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Talebi","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-7734","authenticated-orcid":false,"given":"Shuiying","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Division of Outcomes and Translational Sciences, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2660-6644","authenticated-orcid":false,"given":"Alex","family":"Sparreboom","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-3252","authenticated-orcid":false,"given":"Sharyn D.","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1176-675X","authenticated-orcid":false,"given":"Eric D.","family":"Eisenmann","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2040620720930614","DOI":"10.1177\/2040620720930614","article-title":"Gilteritinib in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia with a FLT3 Mutation","volume":"11","author":"Chew","year":"2020","journal-title":"Ther. 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