Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.

Area of Science:

• Pharmacology and Toxicology
• Computational Biology
• Hepatology

Background:

• Mammalian liver metabolism and xenobiotic detoxification exhibit spatial variations at multiple scales.
• Existing computational models often overlook this heterogeneity, treating the liver as a homogeneous organ.
• Pathological liver conditions can present zonated or heterogeneous cellular changes.

Purpose of the Study:

• To develop a methodology for integrating detailed liver models into whole-body pharmacokinetic (PK) models.
• To create a four-scale computational model (cell, sinusoid, organ, organism) for representing liver metabolization inhomogeneity.
• To mechanistically represent spatial variations in liver function across different scales.

Main Methods:

• Combined different computational modeling approaches from existing literature.
• Developed an integrated four-scale model encompassing cellular to whole-organism levels.
• Incorporated circulatory mixing effects and delayed recirculation from the organism.

Main Results:

• Demonstrated the model's applicability across species, compounds, and disease states (e.g., midazolam in steatotic human livers, caffeine in regenerating mouse livers, insulin uptake in mouse livers).
• Showcased how local-scale variations impact substance distribution at the whole-body plasma level.
• Highlighted the necessity of considering all relevant spatial scales for accurate organism-level predictions.

Conclusions:

• The developed four-scale model successfully represents liver metabolization inhomogeneity.
• This integrated approach enhances the accuracy of whole-body pharmacokinetic predictions by accounting for spatial heterogeneity.
• Simultaneous consideration of multi-scale variations is crucial for understanding organism-level physiological and toxicological processes.