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

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. Graphical Abstract