1. The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions
- Author
-
Maria R. Baer, Suneet Shukla, Jasjeet Bhullar, Karthika Natarajan, Trevor J. Mathias, Suresh V. Ambudkar, and Mariola Sadowska
- Subjects
Abcg2 ,Cancer Treatment ,lcsh:Medicine ,Pharmacology ,Biochemistry ,Hematologic Cancers and Related Disorders ,chemistry.chemical_compound ,0302 clinical medicine ,Chemosensitization ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Drug Interactions ,Biomacromolecule-Ligand Interactions ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Heart ,Hematology ,3. Good health ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,Medicine ,Oncology Agents ,FLT3 Inhibitor ,Research Article ,Fluoroquinolones ,Acute Myeloid Leukemia ,Drugs and Devices ,ATP Binding Cassette Transporter, Subfamily B ,Cell Survival ,Biophysics ,Antineoplastic Agents ,Biology ,Absorption ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Leukemias ,Animals ,Humans ,Viability assay ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Benzothiazoles ,Protein Kinase Inhibitors ,030304 developmental biology ,Quizartinib ,Dose-Response Relationship, Drug ,Phenylurea Compounds ,lcsh:R ,Biological Transport ,Chemotherapy and Drug Treatment ,chemistry ,fms-Like Tyrosine Kinase 3 ,Apoptosis ,biology.protein ,ATP-Binding Cassette Transporters ,lcsh:Q ,sense organs - Abstract
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 [125I]iodoarylazidoprazosin ([125I]-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 [125I]-IAAP photolabeling of ABCG2 and ABCB1 with IC50 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.
- Published
- 2013