title: The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions.
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.
authors: Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, United States of America.
authors: Jasjeet
authors: J
authors: Bhullar
authors: Karthika
authors: K
authors: Natarajan
authors: Suneet
authors: S
authors: Shukla
authors: Trevor J
authors: TJ
authors: Mathias
authors: Mariola
authors: M
authors: Sadowska
authors: Suresh V
authors: SV
authors: Ambudkar
authors: Maria R
authors: MR
authors: Baer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000042:Absorption / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D052160:Benzothiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D024841:Fluoroquinolones; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C544967:quizartinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
references: Hum Gene Ther. 2000 Mar 1;11(4):555-65
references: 10724034
references: Blood. 2001 Sep 15;98(6):1752-9
references: 11535508
references: Drug Resist Updat. 2012 Feb-Apr;15(1-2):98-105
references: 22483810
references: Blood. 2002 Dec 15;100(13):4372-80
references: 12393388
references: Drug Resist Updat. 2012 Feb-Apr;15(1-2):70-80
references: 22325423
references: Clin Cancer Res. 2004 Dec 1;10(23):7896-902
references: 15585622
references: Mol Cancer Ther. 2012 Sep;11(9):2033-44
references: 22778153
references: Blood. 2002 Aug 15;100(4):1224-32
references: 12149202
references: Xenobiotica. 2008 Jul;38(7-8):802-32
references: 18668431
references: Mol Cancer Ther. 2010 Feb;9(2):319-26
references: 20103600
references: J Biol Chem. 2001 Mar 23;276(12):8657-64
references: 11121420
references: Cancer. 2011 May 15;117(10):2156-62
references: 21523728
references: Biochemistry. 2000 Jan 11;39(1):194-204
references: 10625494
references: Cancer Res. 1999 Mar 1;59(5):1021-8
references: 10070958
references: Blood. 2004 Jan 1;103(1):267-74
references: 12969963
references: J Clin Oncol. 2012 Jul 10;30(20):2441-8
references: 22508825
references: Blood. 2010 Sep 2;116(9):1413-21
references: 20522709
references: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2515-20
references: 10716986
references: Expert Opin Drug Metab Toxicol. 2011 May;7(5):623-42
references: 21410427
references: Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3287-96
references: 18089722
references: Drug Metab Dispos. 2009 Feb;37(2):359-65
references: 18971320
references: Mol Cancer Ther. 2008 Sep;7(9):3092-102
references: 18765824
references: Clin Cancer Res. 2001 Jan;7(1):145-52
references: 11205902
references: Br J Haematol. 2004 Oct;127(1):26-33
references: 15384974
references: Drug Metab Lett. 2010 Dec;4(4):201-12
references: 20670210
references: Physiol Rev. 2006 Oct;86(4):1179-236
references: 17015488
references: Methods Enzymol. 1998;292:504-14
references: 9711578
references: Leukemia. 2012 Oct;26(10):2176-85
references: 22614177
references: Leukemia. 1996 Feb;10(2):238-48
references: 8637232
references: J Histochem Cytochem. 1977 Jul;25(7):935-41
references: 894009
references: Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10338-42
references: 19506252
references: N Engl J Med. 2012 Mar 22;366(12):1079-89
references: 22417203
references: Clin Cancer Res. 2005 Mar 15;11(6):2436-44
references: 15788695
references: Haematologica. 2012 Nov;97(11):1736-42
references: 22733022
references: Blood. 2010 Nov 18;116(20):4077-85
references: 20716770
references: Curr Drug Targets. 2010 Jul;11(7):781-9
references: 20370649
references: Biochemistry. 1998 Apr 7;37(14):5010-9
references: 9538020
references: Clin Cancer Res. 2004 Mar 1;10(5):1826-34
references: 15014037
references: N Engl J Med. 2004 Mar 4;350(10):1013-22
references: 14999113
references: Gut. 2003 Dec;52(12):1788-95
references: 14633964
references: Biochem Pharmacol. 2012 Apr 15;83(8):1084-103
references: 22248732
references: Blood. 2009 Oct 1;114(14):2984-92
references: 19654408
references: Leuk Lymphoma. 2012 Nov;53(11):2186-91
references: 22582970
references: Br J Pharmacol. 2009 Oct;158(4):1153-64
references: 19785662
references: N Engl J Med. 2008 May 1;358(18):1909-18
references: 18450602
references: Blood. 2011 Mar 24;117(12):3294-301
references: 21270442
references: Mol Cancer Ther. 2004 Sep;3(9):1119-25
references: 15367706
references: Blood. 2004 Oct 1;104(7):1940-51
references: 15217827
references: Mol Cancer Ther. 2007 Jun;6(6):1877-85
references: 17575116
references: Cancer Res. 2000 May 15;60(10):2589-93
references: 10825126
references: J Clin Oncol. 2010 May 10;28(14):2389-95
references: 20385984
references: Haematologica. 2006 Jun;91(6):825-8
references: 16704962
references: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3452-8
references: 16740770
references: J Leukoc Biol. 1997 May;61(5):619-23
references: 9129211
references: Oncologist. 2011;16(8):1162-74
references: 21765192
references: Clin Cancer Res. 2005 Mar 15;11(6):2320-6
references: 15788683
references: Blood. 2005 Oct 15;106(8):2646-54
references: 15994288
references: Drug Metab Dispos. 2006 Apr;34(4):690-5
references: 16434544
references: J Clin Oncol. 2004 Mar 15;22(6):1078-86
references: 15020609
references: Annu Rev Pharmacol Toxicol. 1999;39:361-98
references: 10331089
references: Biochemistry. 2006 Jul 25;45(29):8940-51
references: 16846237
references: Blood. 2002 Jul 1;100(1):59-66
references: 12070009
references: Blood. 1996 Feb 1;87(3):1089-96
references: 8562934
references: Leuk Res. 2011 Mar;35(3):301-4
references: 21109304
references: Leukemia. 2004 Jul;18(7):1252-7
references: 15208643