Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
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...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/20/6815 |
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| author | Dominique A. Garrison Yan Jin Zahra Talebi Shuiying Hu Alex Sparreboom Sharyn D. Baker Eric D. Eisenmann |
| author_facet | Dominique A. Garrison Yan Jin Zahra Talebi Shuiying Hu Alex Sparreboom Sharyn D. Baker Eric D. Eisenmann |
| author_sort | Dominique A. Garrison |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T19:43:38Z |
| format | Article |
| id | doaj.art-b65f1f8fc5034a02aae249f90a5b1265 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T19:43:38Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b65f1f8fc5034a02aae249f90a5b12652023-11-24T01:31:37ZengMDPI AGMolecules1420-30492022-10-012720681510.3390/molecules27206815Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1BDominique A. Garrison0Yan Jin1Zahra Talebi2Shuiying Hu3Alex Sparreboom4Sharyn D. Baker5Eric D. Eisenmann6Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210, USAGilteritinib, 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.https://www.mdpi.com/1420-3049/27/20/6815gilteritinibOATP1Bitraconazolepharmacokineticsdrug–drug interactionsCYP3A |
| spellingShingle | Dominique A. Garrison Yan Jin Zahra Talebi Shuiying Hu Alex Sparreboom Sharyn D. Baker Eric D. Eisenmann Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B Molecules gilteritinib OATP1B itraconazole pharmacokinetics drug–drug interactions CYP3A |
| title | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
| title_full | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
| title_fullStr | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
| title_full_unstemmed | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
| title_short | Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B |
| title_sort | itraconazole induced increases in gilteritinib exposure are mediated by cyp3a and oatp1b |
| topic | gilteritinib OATP1B itraconazole pharmacokinetics drug–drug interactions CYP3A |
| url | https://www.mdpi.com/1420-3049/27/20/6815 |
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