Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, United States of America.
PLoS One. 2013 Aug 14;8(8):e71266. doi: 10.1371/journal.pone.0071266. eCollection 2013.
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.
口服第二代双芳基脲 fms 样酪氨酸激酶 3（FLT3）抑制剂 quizartinib（AC220）具有良好的激酶选择性和药代动力学特性。它在体内以 0.1 和 0.5µM 分别抑制突变型和野生型 FLT3，在急性髓细胞白血病的 I 期和 II 期试验中显示出良好的活性和耐受性，以 QT 延长为剂量限制性毒性。计划与化疗联合使用。我们研究了 quizartinib 与 ATP 结合盒（ABC）蛋白 ABCB1（P-糖蛋白）和 ABCG2（乳腺癌耐药蛋白）的相互作用。通过流式细胞术测量其对荧光底物摄取和凋亡的影响，通过对 [¹²⁵I]碘代氮杂芐嗪 ([¹²⁵I]-IAAP) 光标记和 ATP 酶活性的影响，以及通过 WST-1 比色法测量细胞活力，来评估 quizartinib 对 ABCB1 和 ABCG2 药物结合位点的结合。Quizartinib 以浓度依赖性方式抑制 ABCG2 和 ABCB1 过表达细胞中荧光 ABCG2 和 ABCB1 底物的转运，分别为 0.1 至 5µM 和 0.5 至 10µM，并且以 0.07 和 3.3µM 的 IC₅₀ 值分别抑制 [¹²⁵I]-IAAP 对 ABCG2 和 ABCB1 的光标记。Quizartinib 在较高浓度下降低 ABCG2，但不降低 ABCB1 的 ATP 酶活性。在细胞活力和凋亡测定中，与 0.1 至 1µM 的 quizartinib 共同孵育以浓度依赖性方式使 ABCG2 过表达的 K562/ABCG2 和 8226/MR20 细胞对 ABCG2 底物化疗药物敏感。此外，quizartinib 以浓度依赖性方式增加 ABCG2 底物氟喹诺酮类抗生素环丙沙星的细胞摄取，这也会延长 QT 间期，当与 quizartinib 联合使用时，预测会改变环丙沙星的药代动力学和药效学。因此，quizartinib 在具有临床相关性的浓度下抑制 ABCG2，这对化疗增敏和药物相互作用都有影响。在设计联合使用 quizartinib 和化疗药物的治疗方案以及选择与 quizartinib 同时使用的伴随药物时，应考虑这些相互作用。
