CoChat
Sign Up
Cited by 24Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyPharmacogenetics and Drug Metabolism

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

Open access
Rezania, Vahid, Coombe, Dennis, Tuszynski, Jack A.·2016·Theoretical Biology and Medical Modelling
DOI 10.1186/s12976-016-0034-5PMC PMC4778290
Open this paper in CoChat — free accountOpen PDF

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). METHOD: 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. CONCLUSION: 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12976-016-0034-5

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The liver lobules are 0.5-1 mm in diameter and defined by sites of portal venous and arterial inflow and central venous outflow.

    “The liver is composed of parenchymal, non-parenchymal, and immune cells that are organized into anatomic structures called lobules, which are 0.5–1 mm in diameter and defined by sites of portal venous and arterial inflow and central venous outflow1,2.”

    From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [1]

    The Background section, “The liver lobule functional unit” (page unavailable), describes a classic lobule with a central hepatic venule and portal tracts at its corners. The Background also mentions flow from portal vein and hepatic artery segments to a hepatic vein in a model it discusses. Our copy does not give a 0.5–1 mm lobule diameter; its Methods describe a modeled diameter of 1.536 mm. Thus the vascular description is supported, but the stated diameter is not. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 25

  1. [1]Ierapetritou MG Georgopoulos PG Roth CM Androulakis IP Tissue-level modeling of xenobiotic metabolism in liver: an emerging tool for enabling clinical translational research Clin Transl Sci 2009 2 3 228 10.1111/j.1752-8062.2009.00092.x 20443896 PMC3068531 · DOI
  2. [2]Rani HP Sheu T Chang TM Liang PC Numerical investigation of non-Newtonian microcirculatory blood flow in hepatic lobule J Biomechanics 2006 39 551 10.1016/j.jbiomech.2004.11.029 16389096 · DOI
  3. [3]Yan L Ropella GE Park S Roberts MS Hunt CA Modelling and simulation of hepatic drug disposition using a physiolocally based Multi Agent In Silico Liver Pharamceutical Res 2007 25 1023 18044012
  4. [4]Wambaugh J Shah I Simulating microdosimetry in a virtual hepatic lobule J Biomechanics 2010 6 4 e1000756 PMC2858695 20421935
  5. [5]Hoehme S Brulport M Bauer A Bedawy E Schormann W Gebhardt R Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration PNAS 2010 107 10371 10.1073/pnas.0909374107 20484673 PMC2890786 · DOI
  6. [6]Schliess F Hoehme S Henkel SG Integrated metabolic spatial-temporal model for the prediction of ammonia detoxification during liver damage and regeneration Hepatology 2014 60 2040 10.1002/hep.27136 24677161 · DOI
  7. [7]Drasdo D Hoehme S Hegstler JG How predictive quantitative modelling of tissue organization can inform liver disease pathogenesis J Hepatology 2014 61 951 10.1016/j.jhep.2014.06.013 24950483 · DOI
  8. [8]Rezania V Marsh RE Coombe D Tuszynski JA A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model Theor Biol Med Model 2013 10 52 10.1186/1742-4682-10-52 24007328 PMC3849449 · DOI
  9. [9]Rezania V Marsh RE Coombe D Tuszynski JA A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models Theor Biol Med Model 2013 10 53 10.1186/1742-4682-10-53 24007357 PMC3833673 · DOI
  10. [10]Saxena R Theise ND Crawford JM Micro-anatomy of the human liver – exploring the hidden interfaces Hepatology 1999 30 1339 10.1002/hep.510300607 10573509 · DOI
  11. [11]Bhunchet E Wake K The portal lobule in rat liver fibrosis: a re-evaluation of the liver unit Hepatology 1998 27 2 481 7 10.1002/hep.510270223 9462647 · DOI
  12. [12]Teutsch HF The modular microarchitecture of human liver Hepatology 2005 42 317 10.1002/hep.20764 15965926 · DOI · Paper page
  13. [16]Jungermann K Thurman R Oxygen: modulator of metabolic zonation and disease in the liver Hepatology 2000 31 2 255 10.1002/hep.510310201 10655244 · DOI · Paper page
  14. [17]Rowinsky EK Wright M Monsarrat B Lesser GJ Donehower RC Taxol: Pharmacology, metabolism, and clinical implications Cancer Surv 1993 17 283 304 7907949
  15. [18]Huizing MT Misser VH Pieters RC ten Bokkel Huinink WW Veenhopf CH Vermorkem JP Pinedo HM Beijnen JH Taxanes: a new class of antitumour agents Cancer Invest 1995 13 381 404 10.3109/07357909509031919 7627725 · DOI
  16. [19]Vaclavikova R Soucek P Svobodova L Anzenbacher P Simek P Guengerich F Gut I Different in vitro metabolism of paclitaxel and docetaxoel in humans, rats, pigs, and minipigs Drug Metab Dispos 2004 32 6 666 74 10.1124/dmd.32.6.666 15155559 · DOI
  17. [20]Monsarrat B Chatelut E Royer I Alvinerie P Dubois J Dezeus A Roche H Cros S Wright W Canal P Modification of paclitaxol metabolism in cancer patient by induction of cytochrome P450 3A4 Drug Met Disp 1998 26 229 33 9492385
  18. [21]Jungermann K Thurman R Hepatocyte heterogeneity in the metabolism of carbohydrates Enzyme 1992 46 33 1289081
  19. [22]Haussinger D Lamers W Moorman A Hepatocyte heterogeneity in the metabolism of amino acids and ammonia Enzyme 1992 46 72 1289083
  20. [23]Schwen LO Krauss M Niederalt C Gremse F Kiessling F Spatio-temporal simulation of first pass drug perfusion in the liver PLoS Comput Biol 2014 10 3 e1003499 10.1371/journal.pcbi.1003499 24625393 PMC3952820 · DOI
  21. [24]Schwen LO Schenk A Kreutz C Timmer J Bartolomé-Rodríguez MM Kuepfer L Preusser T Representative sinusoids for hepatic four-scale pharmacokinetics simulations PLoS ONE 2015 10 7 e0133653 10.1371/journal.pone.0133653 26222615 PMC4519332 · DOI
  22. [26]Pang KS Weiss M Macheras P Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts AAPS J 2007 9 2 E268 83 10.1208/aapsj0902030 17907768 PMC2751417 · DOI · Paper page
  23. [27]Vos KJ Martin AG Trimbol MG Forestell L Barakat K Tuszynski JA A multi-compartment pharmacokinetic model of the interaction between paclitaxel and doxorubicin EPJ Nonlinear Biomed Phys 2014 2 13 10.1140/epjnbp/s40366-014-0013-x · DOI
  24. [28]Davidson AJ Ellis MJ Chaudhuri JB A theoretical method to improve and optimize the design of bioartificial livers Biotech Bioeng 2010 106 6 980 10.1002/bit.22765 20506230 · DOI
  25. [29]Davidson AJ Ellis MJ Chaudhuri JB A theoretical approach to zonation in a bioartificial liver Biotech Bioeng 2011 109 1 234 10.1002/bit.23279 PMC3579238 21809328 · DOI

Cited by

Sorted by citations

Authors
Rezania, V., Coombe, D., & Tuszynski, J. A.
Affiliations
  • MacEwan University (CA)
  • Computer Modelling Group (Canada) (CA)
Corresponding author
Rezania, Vahid
ORCID
Rezania, Vahid
Venue
Theoretical Biology and Medical Modelling
Publisher
Springer Science and Business Media LLC
Published
2016-03-03
Volume
13
Issue
1
Pages
9-9
ISSN
1742-4682 (ISSN-L)
DOI
10.1186/s12976-016-0034-5
PMC
PMC4778290
OpenAlex
W2292226965
Cited by
24
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 2
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Theoretical Biology and Medical Modelling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Natural Sciences and Engineering Research Council of Canada
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
liver lobule, hepatic drug elimination, diffusion-limited aggregation, hexagonal lattice model, liver zonation, drug metabolism, hepatic blood flow, oxygen distribution, drug-induced liver injury, hepatotoxicity
MeSH terms
Algorithms, Antineoplastic Agents, Biological Transport, Computer Simulation, Diffusion, Pharmaceutical Preparations, Humans, Liver, Inactivation, Metabolic, Neoplasms, Oxygen, Chemical and Drug Induced Liver Injury

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review