Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):1017-23. doi: 10.1007/s00210-012-0781-8. Epub 2012 Jul 18.
Besides the three antidepressant-sensitive, Na(+)- and Cl(-)-dependent monoamine transporters, Na(+)-independent organic cation transporters (OCTs) are known to transport monoamines. However, little is known about the interactions of psychotropic drugs with human (h) OCTs. In the present study, a series of diverse antidepressant and antipsychotic drugs were examined for their inhibitory potency at hOCT1, hOCT2 and hOCT3 by measuring inhibition of [(3)H]-MPP(+) uptake into HEK293 cells stably expressing one of the three hOCTs. The inhibitory potencies (IC(50)s) ranged from 1 to 900 μM. Most of the examined drugs showed highest inhibitory potency at hOCT1 which is very sparsely expressed in the brain and mainly involved in renal and hepatic clearance of cationic drugs. At their upper therapeutic plasma concentrations, several drugs are expected to inhibit by more than 20 % hOCT1 and could thus interfere with the pharmacokinetics of hOCT1-transported drugs in the kidney and liver, namely trimipramine, desipramine and fluoxetine (by about 37 %), levomepromazine and nefazodone (by about 32 %), and clozapine and amitriptyline (by about 22 %). At hOCT2 and hOCT3, which are involved in monoamine homeostasis in the brain, IC(50)s of most psychoactive drugs were in the high micromolar range. At their upper plasma concentrations, only three compounds, bupropion, nefazodone and clozapine, showed potential for inhibition, of about 18 % at hOCT2 (bupropion), about 22 % at hOCT3 (nefazodone) and of approximately 10 % at hOCT2 and hOCT3 (clozapine). Thus, under the assumption of a tenfold accumulation in the brain, bupropion, nefazodone and clozapine may notably inhibit the corresponding hOCTs. It remains to be shown whether such a direct inhibition plays a role in the clinical effects of these three drugs.
除了三种对抗抑郁药物敏感、钠（+）和氯离子（-）依赖的单胺转运体之外，还已知钠离子非依赖性有机阳离子转运体（OCTs）可以转运单胺。然而，人们对精神药物与人类（h）OCTs 的相互作用知之甚少。在本研究中，通过测量对稳定表达三种 hOCT 之一的 HEK293 细胞中 [(3)H]-MPP(+)摄取的抑制作用，检查了一系列不同的抗抑郁药和抗精神病药对 hOCT1、hOCT2 和 hOCT3 的抑制效力。抑制效力（IC50）范围为 1 至 900μM。大多数检查的药物对 hOCT1 表现出最高的抑制效力，hOCT1 在大脑中表达非常稀疏，主要参与阳离子药物在肾脏和肝脏中的清除。在其较高的治疗血浆浓度下，几种药物预计会抑制超过 20%的 hOCT1，从而可能干扰肾脏和肝脏中 hOCT1 转运的药物的药代动力学，即三甲丙咪嗪、去甲丙咪嗪和氟西汀（约 37%）、左美丙嗪和奈法唑酮（约 32%）以及氯氮平和阿米替林（约 22%）。在 hOCT2 和 hOCT3 中，它们参与大脑中单胺的动态平衡，大多数精神活性药物的 IC50 处于高微摩尔范围内。在其较高的血浆浓度下，只有三种化合物，即安非他酮、奈法唑酮和氯氮平，表现出抑制的潜力，在 hOCT2 中约为 18%（安非他酮），在 hOCT3 中约为 22%（奈法唑酮），在 hOCT2 和 hOCT3 中约为 10%（氯氮平）。因此，假设在大脑中积累十倍，安非他酮、奈法唑酮和氯氮平可能显著抑制相应的 hOCTs。尚不清楚这种直接抑制是否在这三种药物的临床效果中起作用。
