Both entecavir and crizotinib are substrates of organic cation transporter 2 (OCT2). The aim of present study was to investigate the mechanisms of drug interactions between these two drugs. Kinetic analysis of entecavir on crizotinib uptake was conduct. Plasma concentration of crizotinib in rats and lung cancer patients, uptake of crizotinib in kidney slices and OCT2 transfected cells, were determined by LC-MS/MS. The clinical pharmacokinetic interactions and impact on adverse reaction of crizotinib in lung cancer patients were investigated. Steady-state through concentration of crizotinib was measured. The crizotinib-related adverse reactions were recorded in lung cancer patients with and without entecavir. Entecavir and 1-methyl-4-phenylpyridinium iodide significantly inhibited the uptake of crizotinib in kidney slices. Kinetic constants for crizotinib uptake by OCT2 were Km 1.16 ± 0.26 µM, Vmax 12.05 ± 0.53 µmol/min mg-1 protein and Ki 9.711 nM. Entecavir can inhibit crizotinib transport by OCT2 in kidney. Co-administration of entecavir significantly reduced the elimination of crizotinib in rats. In lung cancer patients, the steady-state AUCss of crizotinib increased approximately 1.2 fold (p < 0.05) but clearance was decreased by approximately 15% in the presence of entecavir. Steady-state through concentration of crizotinib significantly increased 1.3-fold when co-administrated with entecavir (p>0.001). Co-medication of entecavir significantly (p < 0.05) increased the risks of vision disorders, diarrhea and vomiting 1.6-, 2.3- and 1.8-fold. Entecavir could increase the exposure and reduce the elimination of crizotinib in lung cancer patients. Moreover, the presence of entecavir could significantly increase the incidences of adverse reaction of crizotinib.

中文翻译：

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克唑替尼和恩替卡韦之间通过肾脏分泌转运蛋白OCT2的药物相互作用。

恩替卡韦和克唑替尼都是有机阳离子转运蛋白2（OCT2）的底物。本研究的目的是研究这两种药物之间药物相互作用的机制。进行恩替卡韦对克唑替尼摄取的动力学分析。通过LC-MS / MS测定了大鼠和肺癌患者中crizotinib的血浆浓度，肾脏切片中crizotinib的摄取以及OCT2转染的细胞的摄取。研究了克唑替尼在肺癌患者中的临床药代动力学相互作用及其对不良反应的影响。测量了克唑替尼的稳态透过浓度。在有和没有恩替卡韦的肺癌患者中记录了克唑替尼相关的不良反应。恩替卡韦和1-甲基-4-苯基碘化碘显着抑制了克唑替尼在肾脏切片中的摄取。OCT2摄取克唑替尼的动力学常数为Km 1.16±0.26 µM，Vmax 12.05±0.53 µmol / min mg-1蛋白和Ki 9.711 nM。恩替卡韦可通过OCT2抑制克唑替尼在肾脏中的转运。恩替卡韦的共同给药显着减少了克唑替尼在大鼠中的消除。在肺癌患者中，克唑替尼的稳态AUCs增加约1.2倍（p <0.05），但是在存在恩替卡韦的情况下清除率降低了约15％。与恩替卡韦合用时，crizotinib的稳态透过浓度显着增加了1.3倍（p> 0.001）。恩替卡韦的联合用药显着（p <0.05）增加了视力障碍，腹泻和呕吐的1.6倍，2.3倍和1.8倍的风险。恩替卡韦可增加肺癌患者的暴露量并减少克唑替尼的消除。