Cargando…
The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions
The oral second-generation bis-aryl urea fms-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) has favorable kinase selectivity and pharmacokinetics. It inhibits mutant and wild-type FLT3 in vivo at 0.1 and 0.5 µM, respectively, and has shown favorable activity and tolerability in phase I...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743865/ https://www.ncbi.nlm.nih.gov/pubmed/23967177 http://dx.doi.org/10.1371/journal.pone.0071266 |
_version_ | 1782280532013350912 |
---|---|
author | Bhullar, Jasjeet Natarajan, Karthika Shukla, Suneet Mathias, Trevor J. Sadowska, Mariola Ambudkar, Suresh V. Baer, Maria R. |
author_facet | Bhullar, Jasjeet Natarajan, Karthika Shukla, Suneet Mathias, Trevor J. Sadowska, Mariola Ambudkar, Suresh V. Baer, Maria R. |
author_sort | Bhullar, Jasjeet |
collection | PubMed |
description | The oral second-generation bis-aryl urea fms-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) has favorable kinase selectivity and pharmacokinetics. It inhibits mutant and wild-type FLT3 in vivo at 0.1 and 0.5 µM, respectively, and has shown favorable activity and tolerability in phase I and II trials in acute myeloid leukemia, with QT prolongation as the dose-limiting toxicity. Co-administration with chemotherapy is planned. We characterized interactions of quizartinib with the ATP-binding cassette (ABC) proteins ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Its effects on uptake of fluorescent substrates and apoptosis were measured by flow cytometry, binding to ABCB1 and ABCG2 drug-binding sites by effects on [(125)I]iodoarylazidoprazosin ([(125)I]-IAAP) photolabeling and ATPase activity, and cell viability by the WST-1 colorimetric assay. Quizartinib inhibited transport of fluorescent ABCG2 and ABCB1 substrates in ABCG2- and ABCB1-overexpressing cells in a concentration-dependent manner, from 0.1 to 5 µM and from 0.5 to 10 µM, respectively, and inhibited [(125)I]-IAAP photolabeling of ABCG2 and ABCB1 with IC(50) values of 0.07 and 3.3 µM, respectively. Quizartinib at higher concentrations decreased ABCG2, but not ABCB1, ATPase activity. Co-incubation with quizartinib at 0.1 to 1 µM sensitized ABCG2-overexpressing K562/ABCG2 and 8226/MR20 cells to ABCG2 substrate chemotherapy drugs in a concentration-dependent manner in cell viability and apoptosis assays. Additionally, quizartinib increased cellular uptake of the ABCG2 substrate fluoroquinolone antibiotic ciprofloxacin, which also prolongs the QT interval, in a concentration-dependent manner, predicting altered ciprofloxacin pharmacokinetics and pharmacodynamics when co-administered with quizartinib. Thus quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. These interactions should be considered in the design of treatment regimens combining quizartinib and chemotherapy drugs and in choice of concomitant medications to be administered with quizartinib. |
format | Online Article Text |
id | pubmed-3743865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37438652013-08-21 The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions Bhullar, Jasjeet Natarajan, Karthika Shukla, Suneet Mathias, Trevor J. Sadowska, Mariola Ambudkar, Suresh V. Baer, Maria R. PLoS One Research Article The oral second-generation bis-aryl urea fms-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) has favorable kinase selectivity and pharmacokinetics. It inhibits mutant and wild-type FLT3 in vivo at 0.1 and 0.5 µM, respectively, and has shown favorable activity and tolerability in phase I and II trials in acute myeloid leukemia, with QT prolongation as the dose-limiting toxicity. Co-administration with chemotherapy is planned. We characterized interactions of quizartinib with the ATP-binding cassette (ABC) proteins ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Its effects on uptake of fluorescent substrates and apoptosis were measured by flow cytometry, binding to ABCB1 and ABCG2 drug-binding sites by effects on [(125)I]iodoarylazidoprazosin ([(125)I]-IAAP) photolabeling and ATPase activity, and cell viability by the WST-1 colorimetric assay. Quizartinib inhibited transport of fluorescent ABCG2 and ABCB1 substrates in ABCG2- and ABCB1-overexpressing cells in a concentration-dependent manner, from 0.1 to 5 µM and from 0.5 to 10 µM, respectively, and inhibited [(125)I]-IAAP photolabeling of ABCG2 and ABCB1 with IC(50) values of 0.07 and 3.3 µM, respectively. Quizartinib at higher concentrations decreased ABCG2, but not ABCB1, ATPase activity. Co-incubation with quizartinib at 0.1 to 1 µM sensitized ABCG2-overexpressing K562/ABCG2 and 8226/MR20 cells to ABCG2 substrate chemotherapy drugs in a concentration-dependent manner in cell viability and apoptosis assays. Additionally, quizartinib increased cellular uptake of the ABCG2 substrate fluoroquinolone antibiotic ciprofloxacin, which also prolongs the QT interval, in a concentration-dependent manner, predicting altered ciprofloxacin pharmacokinetics and pharmacodynamics when co-administered with quizartinib. Thus quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. These interactions should be considered in the design of treatment regimens combining quizartinib and chemotherapy drugs and in choice of concomitant medications to be administered with quizartinib. Public Library of Science 2013-08-14 /pmc/articles/PMC3743865/ /pubmed/23967177 http://dx.doi.org/10.1371/journal.pone.0071266 Text en © 2013 Bhullar et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bhullar, Jasjeet Natarajan, Karthika Shukla, Suneet Mathias, Trevor J. Sadowska, Mariola Ambudkar, Suresh V. Baer, Maria R. The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title | The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title_full | The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title_fullStr | The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title_full_unstemmed | The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title_short | The FLT3 Inhibitor Quizartinib Inhibits ABCG2 at Pharmacologically Relevant Concentrations, with Implications for Both Chemosensitization and Adverse Drug Interactions |
title_sort | flt3 inhibitor quizartinib inhibits abcg2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743865/ https://www.ncbi.nlm.nih.gov/pubmed/23967177 http://dx.doi.org/10.1371/journal.pone.0071266 |
work_keys_str_mv | AT bhullarjasjeet theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT natarajankarthika theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT shuklasuneet theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT mathiastrevorj theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT sadowskamariola theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT ambudkarsureshv theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT baermariar theflt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT bhullarjasjeet flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT natarajankarthika flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT shuklasuneet flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT mathiastrevorj flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT sadowskamariola flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT ambudkarsureshv flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions AT baermariar flt3inhibitorquizartinibinhibitsabcg2atpharmacologicallyrelevantconcentrationswithimplicationsforbothchemosensitizationandadversedruginteractions |