Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.
Drug Metab Pharmacokinet. 2020 Jun;35(3):266-273. doi: 10.1016/j.dmpk.2020.01.005. Epub 2020 Jan 29.
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 °C was higher than that at 4 °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 ≈ 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.
拉莫三嗪（LTG）是治疗癫痫孕妇癫痫发作的重要抗癫痫药物。然而，尚不清楚 LTG 是否通过载体介导途径进入胎盘细胞。本研究旨在研究 LTG 进入胎盘细胞系（BeWo 和 JEG-3）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，SLC22A4-5）在摄取过程中的参与情况。在 37°C 时 LTG 的摄取高于 4°C。在两种细胞系中均检测到 OCT1 和 OCTNs。LTG 的摄取不受细胞外 pH、无 Na 条件或 l-肉碱的存在的影响，这表明 OCTNs 不参与。尽管几种 OCTs 的强效抑制剂（氯喹、丙咪嗪、奎尼丁和维拉帕米）抑制了 LTG 的摄取，但其他典型抑制剂没有影响。此外，靶向 OCT1 的 siRNA 对 LTG 的摄取没有明显影响。人足月胎盘中的 mRNA 表达顺序为 OCTN2>OCT3>OCTN1>OCT1≈OCT2。这些观察结果表明，LTG 进入胎盘细胞的摄取是载体介导的，但 OCTs 和 OCTNs 与胎盘转运过程无关。
