title: A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models.
abstract: BACKGROUND
  One of the major issues in current pharmaceutical development is potential hepatotoxicity and drug-induced liver damage. This is due to the unique metabolic processes performed in the liver to prevent accumulation of a wide range of chemicals in the blood. Recently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit).
  
  
  METHODS
  In this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions. We introduce a hexagonal-based model with one input (portal vein) and six outputs (hepatic veins) to represent a typical liver lobule. To capture even more realistic structures, we implement a novel sequential diffusion-limited aggregation (DLA) method to construct a morphological sinusoid network in the lobule. A 3D model constructed with stacks of multiple 2D sinusoid realizations is explored to study the effects of 3D structural variations. The role of liver zonation on drug metabolism in the lobule is also addressed, based on flow-based predicted steady-state O2 profiles used as a zonation indicator.
  
  
  RESULTS
  With this model, we analyze predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and compare with our earlier idealized models. In 2D, due to randomness of the sinusoidal structure, individual hepatic veins respond differently (i.e. at different times) to injected drug. In 3D, however, the variation of response to the injected drug is observed to be less extreme. Also, the production curves show more diffusive behavior in 3D than in 2D.
  
  
  CONCLUSIONS
  Although, the individual producing ports respond differently, the average lobule production summed over all hepatic veins is more diffuse. Thus the net effect of all these variations makes the overall response smoother. We also show that, in 3D, the effect of zonation on drug production characteristics appears quite small. Our new biophysical structural analysis of a physiologically-based 3D lobule can therefore form the basis for a quantitative assessment of liver function and performance both in health and disease.
authors.affiliation: Department of Physical Sciences, MacEwan University, Edmonton, AB, T5J 4S2, Canada. rezaniav@macewan.ca.
authors.forename: Vahid
authors.initials: V
authors.lastname: Rezania
authors.affiliation: Computer Modelling Group Ltd, Calgary, AB, T2L 2A6, Canada. Dennis.Coombe@cmgl.ca.
authors.forename: Dennis
authors.initials: D
authors.lastname: Coombe
authors.affiliation: Department of Physics and Experimental Oncology, University of Alberta, Edmonton, AB, T6G 2J1, Canada. jackt@ualberta.ca.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001692:Biological Transport; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology; D003198:Computer Simulation; D004058:Diffusion; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010100:Oxygen / Q000737:chemistry; D004364:Pharmaceutical Preparations
chemical_list: D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D010100:Oxygen