Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL 32610-0486, United States.
Pharmacol Res. 2012 Apr;65(4):491-6. doi: 10.1016/j.phrs.2012.01.008. Epub 2012 Feb 8.
Organic cation transporter 3 (OCT3, SLC22A3) is a low-affinity, high-capacity transporter widely expressed in the central nervous system (CNS) and other major organs in both humans and rodents. It is postulated that OCT3 has a role in the overall regulation of neurotransmission and maintenance of homeostasis within the CNS. It is generally believed that all antidepressant drugs in current clinical use exert their primary therapeutic effects through inhibition of one or more of the high-affinity neuronal plasma membrane monoamine transporters, such as the norepinephrine transporter and the serotonin transporter. In the present study, we investigated the inhibitory effects of selected antidepressants on OCT3 activity in OCT3-transfected cells to evaluate whether OCT3 inhibition may at least in part contribute to the pharmacological effects of tested antidepressants. The studies demonstrated that all examined antidepressants inhibited OCT3-mediated uptake of the established OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in a concentration-dependent manner. The IC(50) values were determined to be 4.7 μM, 7.4 μM, 12.0 μM, 18.6 μM, 11.2 μM, and 21.9 μM for desipramine, sertraline, paroxetine, amitriptyline, imipramine, and fluoxetine, respectively. Additionally, desipramine had an IC(50) value of 0.7 μM for the uptake of NE by OCT3, while the IC(50) value of sertraline was 2.3 μM for 5-HT uptake. Both desipramine and sertraline appeared to inhibit OCT3 activity via a non-competitive mechanism. In vivo studies are warranted to determine whether such effects on OCT3 inhibition are of sufficient magnitude to contribute to the overall therapeutic effects of antidepressants.
有机阳离子转运体 3（OCT3，SLC22A3）是一种低亲和力、高容量转运体，广泛表达于人和啮齿动物的中枢神经系统（CNS）和其他主要器官中。据推测，OCT3 在中枢神经系统内的神经传递整体调节和内环境稳定维持中发挥作用。目前临床上使用的所有抗抑郁药被普遍认为主要通过抑制一种或多种高亲和力神经元质膜单胺转运体（如去甲肾上腺素转运体和 5-羟色胺转运体）发挥其主要治疗作用。在本研究中，我们研究了选定的抗抑郁药对 OCT3 转染细胞中 OCT3 活性的抑制作用，以评估 OCT3 抑制是否至少部分有助于所测试抗抑郁药的药理作用。研究表明，所有被检查的抗抑郁药均以浓度依赖性方式抑制 OCT3 介导的 4-（4-（二甲基氨基）-1-萘基）-N-甲基吡啶鎓碘化物（4-Di-1-ASP）的摄取。IC50 值分别为 4.7 μM、7.4 μM、12.0 μM、18.6 μM、11.2 μM 和 21.9 μM 用于去甲丙咪嗪、舍曲林、帕罗西汀、阿米替林、丙咪嗪和氟西汀。此外，去甲丙咪嗪对 OCT3 摄取 NE 的 IC50 值为 0.7 μM，舍曲林对 5-HT 摄取的 IC50 值为 2.3 μM。去甲丙咪嗪和舍曲林似乎通过非竞争性机制抑制 OCT3 活性。需要进行体内研究以确定对 OCT3 抑制的这种作用是否具有足够的幅度来有助于抗抑郁药的整体治疗效果。
