Radiolabeled meta-iodobenzylguanidine (mIBG) is an important radiopharmaceutical used in the diagnosis and treatment of neuroendocrine cancers. mIBG is known to enter tumor cells through the norepinephrine transporter. Whole-body scintigraphy has shown rapid mIBG elimination through the kidney and high accumulation in several normal tissues, but the underlying molecular mechanisms are unclear. Using transporter-expressing cell lines, we show that mIBG is an excellent substrate for human organic cation transporters 1-3 (hOCT1-3) and the multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K), but not for the renal organic anion transporter 1 and 3 (hOAT1/3). Kinetic analysis revealed that hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2-K transport mIBG with similar apparent affinities (K m of 19.5 ± 6.9, 17.2 ± 2.8, 14.5 ± 7.1, 17.7 ± 10.9, 12.6 ± 5.6 µM, respectively). Transwell studies in hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells showed that mIBG transport in the basal (B)-to-apical (A) direction is much greater than in the A-to-B direction. Compared with control cells, the B-to-A permeability of mIBG increased by 20-fold in hOCT2/hMATE1 double-transfected cells. Screening of 23 drugs used in the treatment of neuroblastoma identified several drugs with the potential to inhibit hOCT- or hMATE-mediated mIBG uptake. Interestingly, irinotecan selectively inhibited hOCT1, whereas crizotinib potently inhibited hOCT3-mediated mIBG uptake. Our results suggest that mIBG undergoes renal tubular secretion mediated by hOCT2 and hMATE1/2-K, and hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. SIGNIFICANCE STATEMENT: mIBG is eliminated by the kidney and extensively accumulates in several tissues known to express hOCT1 and hOCT3. Our results suggest that hOCT2 and human multidrug and toxin extrusion proteins 1 and 2-K are involved in mIBG renal elimination, whereas hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. These findings may help to predict and prevent adverse drug interaction with therapeutic [131I]mIBG and develop clinical strategies to reduce [131I]mIBG accumulation and toxicity in normal tissues and organs.

中文翻译：

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多特异性有机阳离子转运蛋白对间碘苄基胍 (mIBG) 转运的表征：对 mIBG 治疗的影响。

放射性标记的间碘苄基胍 (mIBG) 是一种重要的放射性药物，用于诊断和治疗神经内分泌癌。已知 mIBG 通过去甲肾上腺素转运蛋白进入肿瘤细胞。全身闪烁扫描显示通过肾脏快速清除 mIBG 并在几种正常组织中大量积累，但潜在的分子机制尚不清楚。使用表达转运蛋白的细胞系，我们表明 mIBG 是人类有机阳离子转运蛋白 1-3 (hOCT1-3) 以及多药和毒素挤出蛋白 1 和 2-K (hMATE1/2-K) 的极好底物，但不是用于肾脏有机阴离子转运蛋白 1 和 3 (hOAT1/3)。动力学分析显示 hOCT1、hOCT2、hOCT3、hMATE1 和 hMATE2-K 以相似的表观亲和力运输 mIBG（K m 为 19.5 ± 6.9、17.2 ± 2.8、14.5 ± 7.1、17.7 ± 10.9、5.2.6）6 µM，分别）。在 hOCT2/hMATE1 双转染的 Madin-Darby 犬肾细胞中进行的 Transwell 研究表明，mIBG 在基底 (B) 到顶端 (A) 方向上的转运远大于在 A 到 B 方向上的转运。与对照细胞相比，在 hOCT2/hMATE1 双转染细胞中，mIBG 的 B-to-A 通透性增加了 20 倍。对用于治疗神经母细胞瘤的 23 种药物进行筛选，确定了几种可能抑制 hOCT 或 hMATE 介导的 mIBG 摄取的药物。有趣的是，伊立替康选择性抑制 hOCT1，而克唑替尼有效抑制 hOCT3 介导的 mIBG 摄取。我们的结果表明，mIBG 经历由 hOCT2 和 hMATE1/2-K 介导的肾小管分泌，并且 hOCT1 和 hOCT3 可能在 mIBG 摄取到正常组织中起重要作用。意义声明：mIBG 被肾脏清除，并在多种已知表达 hOCT1 和 hOCT3 的组织中大量积累。我们的结果表明 hOCT2 和人类多药和毒素挤出蛋白 1 和 2-K 参与 mIBG 肾脏消除，而 hOCT1 和 hOCT3 可能在 mIBG 摄取到正常组织中起重要作用。这些发现可能有助于预测和预防药物与治疗性 [131I]mIBG 的不良相互作用，并制定临床策略以减少 [131I]mIBG 在正常组织和器官中的积累和毒性。