The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family
The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family
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DOI：
10.1208/s12248-014-9649-9
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发表时间：
2014-11-01
期刊：
影响因子：
4.5
通讯作者：
Tzvetkov, Mladen V.
中科院分区：
文献类型：
--
作者：
Pereira, Joao N. Dos Santos;Tadjerpisheh, Sina;Tzvetkov, Mladen V.
血脑屏障内流运输的变化可能影响精神药物在作用部位的浓度，从而可能改变治疗反应。此外，内脏、肝脏和肾脏等器官中的内流转运蛋白可能影响吸收、分布和消除。在这里，我们使用平行人工膜渗透性试验分析了30种常用的精神药物。氨硫pride和舒必利的膜通透性最低(P (e) < 1.5 x 10(-6) cm/s)，需要内流运输才能穿透血脑屏障和其他生理屏障。然后，我们研究了SLC22家族的有机阳离子转运体OCT1， OCT2, OCT3， OCTN1和OCTN2对氨硫pride和磺胺吡啶的摄取，发现氨硫pride可以被研究的所有五种转运体转运。相比之下，舒必利仅通过OCT1和OCT2转运。OCT1对氨硫pride （CLint = 1.9 ml/min/mg蛋白）和舒匹利（CLint = 4.2 ml/min/mg蛋白）的转运能力最高，且OCT1的多态性显著降低了这两种药物的摄取。此外，我们观察到永生化人脑微血管内皮细胞系hCMEC/D3中已知的OCT抑制剂可以抑制载体介导的摄取。综上所述，本研究表明氨硫脲和硫脲是SLC22家族有机阳离子转运体的底物。SLC22转运蛋白可能在氨硫pride和舒必利的分布中发挥重要作用，包括它们穿透血脑屏障的能力。
Variations in influx transport at the blood-brain barrier might affect the concentration of psychotropic drugs at their site of action and as a consequence might alter therapy response. Furthermore, influx transporters in organs such as the gut, liver and kidney may influence absorption, distribution, and elimination. Here, we analyzed 30 commonly used psychotropic drugs using a parallel artificial membrane permeability assay. Amisulpride and sulpiride showed the lowest membrane permeability (P (e) < 1.5 x 10(-6) cm/s) and will require influx transport to penetrate the blood-brain barrier and other physiological barriers. We then studied the uptake of amisulpride and sulpiride by the organic cation transporters of the SLC22 family OCT1, OCT2, OCT3, OCTN1, and OCTN2 Amisulpride was found to be transported by all five transporters studied. In contrast, sulpiride was only transported by OCT1 and OCT2. OCT1 showed the highest transport ability both for amisulpride (CLint = 1.9 ml/min/mg protein) and sulpiride (CLint = 4.2 ml/min/mg protein) and polymorphisms in OCT1 significantly reduced the uptake of both drugs. Furthermore, we observed carrier-mediated uptake that was inhibitable by known OCT inhibitors in the immortalized human brain microvascular endothelial cell line hCMEC/D3. In conclusion, this study demonstrates that amisulpride and sulpiride are substrates of organic cation transporters of the SLC22 family. SLC22 transporters may play an important role in the distribution of amisulpride and sulpiride, including their ability to penetrate the blood-brain barrier.