Quantitative Prediction of Oral Drug Absorption by Kinetically Analyzing Gastrointestinal Water Dynamics

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07165
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kanazawa University
• Principal Investigator: Shirasaka Yoshiyuki 金沢大学, 薬学系, 准教授 (60453833)
• Co-Investigator(Kenkyū-buntansha): 玉井 郁巳 金沢大学, 薬学系, 教授 (20155237)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 薬物動態学 / 経口吸収 / 消化管 / 水分 / モデリング＆シミュレーション

Outline of Final Research Achievements

Gastrointestinal (GI) fluid volume may be an essential factor in considering GI drug concentration and absorption kinetics. This research project aimed to develop a physiologically based pharmacokinetic (PBPK) absorption model considering GI fluid dynamics based on kinetic analysis of GI fluid absorption/secretion in rats.
Simulated GI fluid volume-time profile in the GI tract using the developed PBPK absorption model incorporating fluid kinetic parameters obtained from the rat in situ studies showed good agreement with that reportedly in vivo data. In addition, it was shown that this model can successfully predict the nonlinear GI absorption, bioavailability, and drug-drug interaction (DDI) of various drugs (CYP3A and/or P-gp substrates).
In conclusion, our PBPK absorption model considering GI fluid dynamics may be very useful for more precise prediction of oral drug absorption and interaction in vivo.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

本研究で確立したILIADモデルは、精緻な薬物吸収動態解析を可能にするとともに、消化管水分動態変動時の薬物吸収への影響を定量的に解析できるものである。したがって、水分動態を変動させる因子である飲料の影響や消化器毒性、疾患・病態、妊娠、さらには人種/年齢/性別などに起因した消化管内水分動態変動時の薬物吸収予測などへの応用が期待できる。本研究成果は、薬物吸収動態予測に基づく医薬品開発への貢献は勿論のこと、薬物相互作用を巡る医薬品の適正使用や消化器疾患に対応する個別化薬物療法など、医療分野を含む多様な貢献にも期待でき、その将来性を含め、学術的にも社会的にも高い意義を有するものである。