A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models

Area of Science:

• Biophysics
• Pharmacology
• Computational Biology

Background:

• Drug-induced liver damage is a significant challenge in pharmaceutical development.
• The liver's unique metabolic processes are crucial for preventing chemical accumulation.
• A physiologically-based lattice model was previously developed for drug transport and metabolism in liver lobules.

Purpose of the Study:

• To extend an existing model by incorporating structural and spatial variability in 2D and 3D.
• To investigate the impact of structural variations and liver zonation on drug metabolism.
• To develop a more realistic model of the liver lobule for quantitative assessment.

Main Methods:

• A hexagonal-based model representing a liver lobule with one input and six outputs was introduced.
• A novel sequential diffusion-limited aggregation (DLA) method was employed to construct a morphological sinusoid network.
• A 3D model was created using stacks of 2D sinusoid realizations, and flow-based O2 profiles indicated liver zonation.

Main Results:

• Drug concentration exiting the lobule was analyzed, showing different responses from individual hepatic veins in 2D due to sinusoidal structure randomness.
• In 3D models, the variation in drug response was less extreme, with more diffusive production curves compared to 2D.
• The study observed that the effect of zonation on drug production characteristics was minimal in 3D.

Conclusions:

• The average lobule production across all hepatic veins is more diffuse, leading to a smoother overall drug response.
• The developed 3D physiologically-based model provides a foundation for quantitatively assessing liver function in health and disease.
• This biophysical structural analysis enhances understanding of drug transport and metabolism within the liver lobule.