Tsang Yik Pui, López Quiñones Antonio Jesús, Vieira Letícia Salvador, Wang Joanne
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
Pharmaceutics. 2023 Sep 13;15(9):2312. doi: 10.3390/pharmaceutics15092312.
Small molecules targeting aberrant anaplastic lymphoma kinase (ALK) are active against ALK-positive non-small-cell lung cancers and neuroblastoma. Several targeted tyrosine kinase inhibitors (TKIs) have been shown to interact with polyspecific organic cation transporters (pOCTs), raising concerns about potential drug-drug interactions (DDIs). The purpose of this study was to assess the interaction of ALK inhibitors with pOCTs and the impact of substrate-dependent inhibition on the prediction of DDIs. Inhibition assays were conducted in transporter-overexpressing cells using meta-iodobenzylguanidine (mIBG), metformin, or 1-methyl-4-phenylpyridinium (MPP+) as the substrate. The half-maximal inhibitory concentrations (IC) of brigatinib and crizotinib for the substrates tested were used to predict their potential for in vivo transporter mediated DDIs. Here, we show that the inhibition potencies of brigatinib and crizotinib on pOCTs are isoform- and substrate-dependent. Human OCT3 (hOCT3) and multidrug and toxin extrusion protein 1 (hMATE1) were highly sensitive to inhibition by brigatinib and crizotinib for all three tested substrates. Apart from hMATE1, substrate-dependent inhibition was observed for all other transporters with varying degrees of dependency; hOCT1 inhibition showed the greatest substrate dependency, with differences in IC values of up to 22-fold across the tested substrates, followed by hOCT2 and hMATE2-K, with differences in IC values of up to 16- and 12-fold, respectively. Conversely, hOCT3 inhibition only showed a moderate substrate dependency (IC variance < 4.8). Among the substrates used, metformin was consistently shown to be the most sensitive substrate, followed by mIBG and MPP+. Pre-incubation of ALK inhibitors had little impact on their potencies toward hOCT2 and hMATE1. Our results underscore the complexity of the interactions between substrates and the inhibitors of pOCTs and have important implications for the clinical use of ALK inhibitors and their DDI predictions.
靶向异常间变性淋巴瘤激酶（ALK）的小分子对ALK阳性非小细胞肺癌和神经母细胞瘤具有活性。几种靶向酪氨酸激酶抑制剂（TKIs）已被证明与多特异性有机阳离子转运体（pOCTs）相互作用，这引发了对潜在药物相互作用（DDIs）的担忧。本研究的目的是评估ALK抑制剂与pOCTs的相互作用以及底物依赖性抑制对DDIs预测的影响。使用间碘苄胍（mIBG）、二甲双胍或1-甲基-4-苯基吡啶鎓（MPP+）作为底物，在过表达转运体的细胞中进行抑制试验。用布加替尼和克唑替尼对所测试底物的半数最大抑制浓度（IC）来预测它们在体内由转运体介导的DDIs的可能性。在此，我们表明布加替尼和克唑替尼对pOCTs的抑制效力是异构体和底物依赖性的。人OCT3（hOCT3）和多药及毒素外排蛋白1（hMATE1）对布加替尼和克唑替尼对所有三种测试底物的抑制高度敏感。除hMATE1外，对所有其他转运体均观察到不同程度的底物依赖性抑制；hOCT1抑制表现出最大的底物依赖性，在所测试底物中IC值差异高达22倍，其次是hOCT2和hMATE2-K，IC值差异分别高达16倍和12倍。相反，hOCT3抑制仅表现出中等程度的底物依赖性（IC差异<4.8）。在所使用的底物中，二甲双胍一直被证明是最敏感的底物，其次是mIBG和MPP+。ALK抑制剂的预孵育对它们对hOCT2和hMATE1的效力影响很小。我们的结果强调了底物与pOCTs抑制剂之间相互作用的复杂性，对ALK抑制剂的临床应用及其DDIs预测具有重要意义。
