Cellular uptake properties of lamotrigine in human placental cell lines: Investigation of involvement of organic cation transporters (SLC22A1-5)
Cellular uptake properties of lamotrigine in human placental cell lines: Investigation of involvement of organic cation transporters (SLC22A1-5)
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DOI：
10.1016/j.dmpk.2020.01.005
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发表时间：
2020-06-01
影响因子：
2.1
通讯作者：
Iseki, Ken
中科院分区：
文献类型：
--
作者：
Hasegawa, Nami;Furugen, Ayako;Iseki, Ken
拉莫三嗪（LTG）是治疗妊娠癫痫发作的重要抗癫痫药物。然而，目前尚不清楚LTG是否通过载体介导的途径转运到胎盘细胞。本研究的目的是研究LTG在胎盘细胞系（BeWo和JEG-3）中的摄取特性，并确定有机阳离子转运体（OCTs, SLC22A1-3）和有机阳离子/肉碱转运体（OCTNs, slc22a1 -5）在摄取过程中的参与。37℃时LTG的摄取高于4℃时，两种细胞系均检测到OCT1和octn。LTG的摄取不受细胞外pH、无Na+条件或左旋肉碱存在的很大影响，这表明octn与此无关。尽管几种有效的OCTs抑制剂（氯喹、丙咪嗪、奎尼丁和维拉帕米）抑制了LTG的摄取，但其他典型的抑制剂没有作用。此外，靶向OCT1的siRNA对LTG摄取没有显著影响。人足月胎盘中mRNA的表达顺序为OCTN2 > OCT3 > OCTN1 > OCT1与OCT2相近。这些观察结果表明，LTG摄取到胎盘细胞是由载体介导的，但oct和octn不负责胎盘运输过程。(C) 2020日本外源性生物研究学会。Elsevier Ltd.出版。版权所有。
Lamotrigine (LTG) is an important antiepileptic drug for the treatment of seizures in pregnant women with epilepsy. However, it is not known if the transport of LTG into placental cells occurs via a carrier-mediated pathway. The aim of this study was to investigate the uptake properties of LTG into placental cell lines (BeWo and JEG-3), and to determine the involvement of organic cation transporters (OCTs, SLC22A1-3) and organic cation/carnitine transporter (OCTNs, SLC22A4-5) in the uptake process. The uptake of LTG at 37 degrees C was higher than that at 4 degrees C. OCT1 and OCTNs were detected in both cell lines. The uptake of LTG was not greatly affected by the extracellular pH, Na+-free conditions, or the presence of L-carnitine, suggesting that OCTNs were not involved. Although several potent inhibitors of OCTs (chloroquine, imipramine, quinidine, and verapamil) inhibited LTG uptake, other typical inhibitors had no effect. In addition, siRNA targeted to OCT1 had no significant effect on LTG uptake. The mRNA expression in human term placenta followed the order OCTN2 > OCT3 > OCTN1 > OCT1 approximate to OCT2. These observations suggested that LTG uptake into placental cells was carrier-mediated, but that OCTs and OCTNs were not responsible for the placental transport process. (C) 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.