Development of therapeutic agents for preeclampsia based on comparative analysis of adverse event reports between antihypertensive drugs

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Keio University
• Principal Investigator: NISHIMURA Tomohiro 慶應義塾大学, 薬学部(芝共立), 准教授 (40453518)
• Co-Investigator(Kenkyū-buntansha): 野口 幸希 慶應義塾大学, 薬学部(芝共立), 助教 (10803661)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 妊娠高血圧症候群 / アンジオテンシンII受容体拮抗薬 / 胎児毒性 / 胎児移行性 / トランスポーター

Outline of Final Research Achievements

Reported frequencies of oligohydramnios against 6 drugs of angiotensin II receptor antagonist (ARB) were investigated. The normalized frequency of irbesartan compared that of olmesartan was significantly low. We analyzed the pharmacological effect, placental transfer and fetal toxicity of irbesartan and olmesartan using the preeclampsia model rats. The irbesartan-administered group had the same fetal weight as the ARB-non-administered group and irbesartan had a lower fetal transfer than olmesartan. It was also shown that irbesartan was transported by OATP2B1 which is expressed in human placenta. The olmesartan-treated group had a reduced fetal weight compared to the ARB-non-treated group. In addition, no transport by OATP2B1 was observed. These findings suggest that irbesartan has a lower fetal transfer and less adverse fetal effect compared to olmesartan.

Free Research Field

生物薬剤学

Academic Significance and Societal Importance of the Research Achievements

現在は、ARBに分類されるすべての薬剤は羊水過少症のリスク増大のため妊婦において禁忌であるが、本研究において、イルベサルタンはARBのうちでも羊水過少が起こりにくいことが示唆された。非臨床試験においてイルベサルタンの胎児移行性が低いことが示され、また胎盤透過に関与するトランスポーターが推定されたことで、イルベサルタンが比較的低リスクであることを支持する結果が得られた。妊娠高血圧症候群において薬剤の選択肢が広がることは重要であり、妊娠高血圧腎症などの重篤例においても、これら薬剤の適切な利用により、妊娠期間を延長し、早産を予防する治療方法に繋がる可能性がある。