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Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models

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Listed:
  • Xiao Fu
  • James P Sluka
  • Sherry G Clendenon
  • Kenneth W Dunn
  • Zemin Wang
  • James E Klaunig
  • James A Glazier

Abstract

Computational models of normal liver function and xenobiotic induced liver damage are increasingly being used to interpret in vitro and in vivo data and as an approach to the de novo prediction of the liver’s response to xenobiotics. The microdosimetry (dose at the level of individual cells) of xenobiotics vary spatially within the liver because of both compound-independent and compound-dependent factors. In this paper, we build model liver lobules to investigate the interplay between vascular structure, blood flow and cellular transport that lead to regional variations in microdosimetry. We then compared simulation results obtained using this complex spatial model with a simpler linear pipe model of a sinusoid and a very simple single box model. We found that variations in diffusive transport, transporter-mediated transport and metabolism, coupled with complex liver sinusoid architecture and blood flow distribution, led to three essential patterns of xenobiotic exposure within the virtual liver lobule: (1) lobular-wise uniform, (2) radially varying and (3) both radially and azimuthally varying. We propose to use these essential patterns of exposure as a reference for selection of model representations when a computational study involves modeling detailed hepatic responses to xenobiotics.

Suggested Citation

  • Xiao Fu & James P Sluka & Sherry G Clendenon & Kenneth W Dunn & Zemin Wang & James E Klaunig & James A Glazier, 2018. "Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models," PLOS ONE, Public Library of Science, vol. 13(9), pages 1-34, September.
    • Handle: RePEc:plo:pone00:0198060
    DOI: 10.1371/journal.pone.0198060
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    References listed on IDEAS

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    1. Lars Ole Schwen & Arne Schenk & Clemens Kreutz & Jens Timmer & María Matilde Bartolomé Rodríguez & Lars Kuepfer & Tobias Preusser, 2015. "Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-39, July.
    2. John Wambaugh & Imran Shah, 2010. "Simulating Microdosimetry in a Virtual Hepatic Lobule," PLOS Computational Biology, Public Library of Science, vol. 6(4), pages 1-16, April.
    3. James P Sluka & Xiao Fu & Maciej Swat & Julio M Belmonte & Alin Cosmanescu & Sherry G Clendenon & John F Wambaugh & James A Glazier, 2016. "A Liver-Centric Multiscale Modeling Framework for Xenobiotics," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-40, September.
    4. Charlotte Debbaut & Jan Vierendeels & Jennifer H. Siggers & Rodolfo Repetto & Diethard Monbaliu & Patrick Segers, 2014. "A 3D porous media liver lobule model: the importance of vascular septa and anisotropic permeability for homogeneous perfusion," Computer Methods in Biomechanics and Biomedical Engineering, Taylor & Francis Journals, vol. 17(12), pages 1295-1310, September.
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