Antiepileptic drug risk assessment and harm reduction strategy for fetal brain function: Focus on cross-placental substance exchange

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14972
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Hokkaido University
• Principal Investigator: Furugen Ayako 北海道大学, 薬学研究院, 助教 (90767261)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 抗てんかん薬 / 胎盤 / トランスポータ / バルプロ酸 / ラモトリギン

Outline of Final Research Achievements

This study investigated the effects of antiepileptic drugs on placental transporter expression and the mechanism of antiepileptic drug transport across the placenta. We investigated the in vivo effects of valproic acid (VPA), which presents several risks to the fetus, on the gene expression of 18 transporters in the placenta. Pregnant rats were orally administered 400 mg/kg/day of VPA for 4 days during mid- or late gestation. VPA administration altered the expression of several transporters in the rat placenta, which suggested differing sensitivity to VPA across gestational stages. We also investigated the factors involved in fetal exposure to lamotrigine (LTG), which is frequently prescribed for treating women with epilepsy. Our results using human placental cell lines indicated that a carrier inhibited by chloroquine, imipramine, quinidine, and verapamil was involved in the transport of LTG.

Free Research Field

医療系薬学

Academic Significance and Societal Importance of the Research Achievements

VPAは、認知機能低下や自閉症といった出生児の脳機能に影響する可能性が示されている抗てんかん薬である。本研究において、VPAはラット胎盤における各種トランスポータ発現量を変化させることを示した。また、妊娠可能年齢女性に選択されるLTGの胎盤由来細胞における輸送特性を明らかにした。本成果を基に、変動したトランスポータ、輸送に寄与することが示されたトランスポータについて、その基質や阻害剤の投与が及ぼす効果を評価することで、リスクを低減させる物質の探索に繋げる。本研究の進展は、抗てんかん薬のリスク評価及び回避策の構築に貢献できるものと考えられる。