دورية أكاديمية
Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
| العنوان: | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
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| المؤلفون: | Dominique A. Garrison, Yan Jin, Zahra Talebi, Shuiying Hu, Alex Sparreboom, Sharyn D. Baker, Eric D. Eisenmann |
| المصدر: | Molecules, Vol 27, Iss 20, p 6815 (2022) |
| بيانات النشر: | MDPI AG, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Organic chemistry |
| مصطلحات موضوعية: | gilteritinib, OATP1B, itraconazole, pharmacokinetics, drug–drug interactions, CYP3A, Organic chemistry, QD241-441 |
| الوصف: | Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. 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–drug 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–drug interactions with itraconazole. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 27206815 1420-3049 |
| Relation: | https://www.mdpi.com/1420-3049/27/20/6815; https://doaj.org/toc/1420-3049 |
| DOI: | 10.3390/molecules27206815 |
| URL الوصول: | https://doaj.org/article/b65f1f8fc5034a02aae249f90a5b1265 |
| رقم الأكسشن: | edsdoj.b65f1f8fc5034a02aae249f90a5b1265 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 27206815 14203049 |
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| DOI: | 10.3390/molecules27206815 |