Prediction model for transplacental drug exposure to the human fetus based on species differences in placental transporters and plasma unbound concentrations

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02651
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Keio University
• Principal Investigator: Tomi Masatoshi 慶應義塾大学, 薬学部(芝共立), 教授 (30334717)
• Co-Investigator(Kenkyū-buntansha): 千葉 康司 横浜薬科大学, 薬学部, 教授 (30458864)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 胎盤 / トランスポーター

Outline of Final Research Achievements

Although the prediction accuracy of the steady-state fetal/maternal plasma concentration ratio (F/M ratio) of some low-membrane-permeability drugs by human placental perfusion has been low, the present study demonstrated that the steady-state F/M ratio of can be estimated by combining the originally developed pharmacokinetic model. Moreover, we clarified that one of the reasons for the lower F/M ratio in rats compared to humans is the species difference in protein binding. This can be overcome by employing the unbound F/M ratio in rats. Furthermore, we observed that the specific expression of MATE1 in rat placenta and the rodent-specific localization of placental MDR1 contribute to the species differences in the fetal transfer of substrate drugs.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

本研究で構築した胎盤透過薬物動態モデルを活用することで、信頼性の高いヒトF/M比を、より効率的に収集することが可能となった。また、実験動物で得られた薬物の発生毒性や胎児移行性からヒトでの影響を定量的に検討する上で、非結合形薬物濃度を基準とし、種差のある胎盤トランスポーターに対する基質認識性への配慮が重要であることを明らかとした。これら成果は、薬物の胎児移行性情報をより信頼度の高い形で得ることを可能とするものであり、妊婦における安全かつ有効な薬物治療を拡大していく上で意義は大きい。