Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
Centre de Pharmacocinétique, Technologie Servier, Orléans, France.
Fundam Clin Pharmacol. 2021 Oct;35(5):919-929. doi: 10.1111/fcp.12657. Epub 2021 Mar 13.
Organic cation transporter (OCT) 3 (SLC22A3) is a widely expressed drug transporter, handling notably metformin and platinum derivatives, as well as endogenous compounds like monoamine neurotransmitters. OCT3 has been shown to be inhibited by a few marketed tyrosine kinase inhibitors (TKIs). The present study was designed to determine whether additional TKIs may interact with OCT3. For this purpose, the effects of 25 TKIs toward OCT3 activity were analyzed using OCT3-overexpressing HEK293 cells. 13/25 TKIs, each used at 10 µM, were found to behave as moderate or strong inhibitors of OCT3 activity, that is, they decreased OCT3-mediated uptake of the fluorescent dye 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide by at least 50% or 80%, respectively. This OCT3 inhibition was correlated to some molecular descriptors of TKIs, such as the percentage of H atoms and that of cationic forms at pH = 7.4. It was concentration-dependent, notably for brigatinib, ceritinib, and crizotinib, which exhibited low half maximal inhibitory concentration (IC ) values in the 28-106 nM range. Clinical concentrations of these three marketed TKIs, as well as those of pacritinib, were next predicted to inhibit in vivo OCT3 activity according to regulatory criteria. Cellular TKI accumulation experiments as well as trans-stimulation assays, however, demonstrated that OCT3 does not transport brigatinib, ceritinib, crizotinib, and pacritinib, thus discarding any implication of OCT3 in the pharmacokinetics of these TKIs. Taken together, these data suggest that some TKIs may act as potent inhibitors of OCT3 activity, which may have consequences in terms of drug-drug interactions and toxicity.
有机阳离子转运蛋白 (OCT) 3 (SLC22A3) 是一种广泛表达的药物转运蛋白，主要负责转运二甲双胍和铂类衍生物等药物，以及单胺类神经递质等内源性化合物。已经证实一些已上市的酪氨酸激酶抑制剂 (TKI) 可抑制 OCT3。本研究旨在确定其他 TKI 是否可能与 OCT3 相互作用。为此，使用过表达 OCT3 的 HEK293 细胞分析了 25 种 TKI 对 OCT3 活性的影响。发现 13/25 种 TKI（每种使用 10 µM）均可中度或强烈抑制 OCT3 活性，即它们分别使 OCT3 介导的荧光染料 4-(4-(二甲基氨基) 亚苄基)-N-甲基吡啶𬭩碘化物摄取减少至少 50%或 80%。这种 OCT3 抑制与 TKI 的一些分子描述符相关，例如 pH = 7.4 时 H 原子和阳离子形式的百分比。它呈浓度依赖性，尤其是对布加替尼、塞瑞替尼和克唑替尼，它们的半最大抑制浓度 (IC ) 值在 28-106 nM 范围内较低。根据监管标准，接下来预测这三种已上市 TKI（以及帕克里替尼）的临床浓度会抑制体内 OCT3 活性。然而，细胞 TKI 积累实验和转染刺激实验表明，OCT3 不转运布加替尼、塞瑞替尼、克唑替尼和帕克里替尼，从而排除了 OCT3 对这些 TKI 药代动力学的任何影响。综上所述，这些数据表明，一些 TKI 可能作为 OCT3 活性的有效抑制剂，这可能会对药物相互作用和毒性产生影响。
