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Quantitative Analysis of Gastrointestinal Water Dynamics by Means of a Physiologically Based Fluid Kinetic Model

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Abstract

Since the processes of dissolution and membrane permeation are affected by the water content in the gastrointestinal (GI) tract, the water dynamics in the GI tract is expected to have a significant impact on the absorption of orally administered drugs. Here, we aimed to develop a physiologically based fluid kinetic (PBFK) model using GI water kinetic parameters obtained from in situ closed-loop studies in rats in order to quantitatively predict GI water dynamics. By incorporating the experimentally measured site-specific parameters of GI water absorption and secretion into a GI compartment model, we developed a bottom-up PBFK model that successfully simulates the reported GI fluid dynamics in rats and humans observed using positron emission tomography and magnetic resonance imaging, respectively. The simulations indicate that the water volume in both the stomach and duodenum is transiently increased by water ingestion, while that in the intestine below the jejunum is unchanged and remains in a steady state in both rats and humans. Furthermore, sensitivity analysis of the effect of ingested water volume on the volume-time profiles of water in the GI tract indicated that the impact of ingested water is limited to the proximal part of the GI tract. Simulations indicated that changes in water kinetic parameters may alter the impact of the ingested water on GI fluid dynamics, especially in the proximal part. Incorporating this PBFK model into a physiologically based pharmacokinetic (PBPK) absorption model has the potential to predict oral drug absorption in a variety of GI water environments.

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Abbreviations

AIC :

Akaike’s information criterion

ATOM:

Advanced translocation model

AUC:

Area under the fluid volume-time curve

AUMC:

Area under the first-moment curve

BCS:

Biopharmaceutics Classification System

DFCAT:

Dynamic fluid compartment absorption and transit

GI:

Gastrointestinal

k abs :

Absorption rate constant of water

k sec :

Secretion rate constant of water

k transit :

Transit rate constant

MRI:

Magnetic resonance imaging

MRT:

Mean residence time

PBFK:

Physiologically based fluid kinetic(s)

PBPK:

Physiologically based pharmacokinetic(s)

PET:

Positron emission tomography

Q por :

Portal vein blood flow

Q villi :

Villous blood flow

S :

Absorptive surface area

S sum :

The sum of the absorptive surface area of the GI tract

SF abs :

Scaling factor for water absorption in humans

SF abs_rat :

In situ-in vivo Scaling factor for water absorption in rats

SF sec :

Scaling factor for water secretion in humans

v :

Velocity

V :

Volume

v abs :

Water absorption rate

V max :

Maximum volume

v sec :

Water secretion rate

V ss :

Steady-state volume

v transit :

Transit rate

WSS :

Weighted sum of squares

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Funding

This work was supported in part by a Grant-in-Aid for JSPS Fellows [JP21J12535] and a Grant-in-Aid for Scientific Research (C) [JP20K07165] from the Japan Society for the Promotion of Science (JSPS), a Research Grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, a grant from the Research Foundation for Pharmaceutical Sciences, and a grant from Nakatomi Foundation.

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Authors and Affiliations

  1. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan

    Satoru Suzuki, Ikumi Tamai & Yoshiyuki Shirasaka

  2. School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Tokyo, 192-0392, Japan

    Satoru Suzuki, Katsuhisa Inoue & Yoshiyuki Shirasaka

Authors
  1. Satoru Suzuki
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  2. Katsuhisa Inoue
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  3. Ikumi Tamai
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  4. Yoshiyuki Shirasaka
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Contributions

Participated in research design: Suzuki, Shirasaka.

Conducted experiments: Suzuki, Shirasaka.

Performed data analysis: Suzuki, Shirasaka.

Wrote or contributed to the writing of the manuscript: Suzuki, Inoue, Tamai, Shirasaka.

Corresponding author

Correspondence to Yoshiyuki Shirasaka.

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Suzuki, S., Inoue, K., Tamai, I. et al. Quantitative Analysis of Gastrointestinal Water Dynamics by Means of a Physiologically Based Fluid Kinetic Model. AAPS J 25, 42 (2023). https://doi.org/10.1208/s12248-023-00809-2

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