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An in‐Silico Model of Xenobiotic Distribution and Metabolism in a Simulated Mouse Hepatic Lobule
Author(s) -
Fu Xiao,
Sluka James P,
Clende Sherry,
Glazier James A.,
Wang Zemin,
Klaunig James,
Ryan Jennifer,
Dunn Kenneth
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1036.8
Subject(s) - xenobiotic , lobules of liver , in silico , hepatocyte , drug metabolism , blood flow , transporter , toxicokinetics , in vivo , metabolism , chemistry , biology , biochemistry , in vitro , medicine , enzyme , endocrinology , gene , microbiology and biotechnology
Liver damage due to xenobiotics and their metabolites is often highly localized. Exposure levels vary within the liver because of the liver's complex flow pattern and because transport and metabolism vary within individual sinusoids. To analyze these coupled effects, we constructed a structurally realistic in silico model of transport and metabolism in the mouse hepatic lobule and simulated the resulting post‐exposure distribution of xenobiotics and their metabolites. Our in silico hepatic lobule architecture is based on our measurements of the ex vivo structure of mouse liver lobules. A hemodynamic model calculates blood flow rates in this simulated liver architecture, validated against intravital microscopy measurements of blood flow in vivo . Submodels simulate transport, uptake and secretion of xenobiotics and metabolites within the in silico hepatic lobule. Differential expression of metabolic enzymes along each sinusoid's portal to central axis, together with differential hepatocyte exposure to xenobiotics, induces non‐uniform production of metabolites. Using the integrated model, we varied both compound‐specific (diffusion, active transport and metabolism) and compound‐independent (temporal alteration of blood flow distribution) parameters to investigate the influence of spatial zonation of enzymes and transporters and temporally varying blood flow on the resulting local exposure to xenobiotics and their metabolites. Variations in transport mechanisms (passive diffusion and transporter‐mediated active transport) and blood flow greatly alter the regional distribution of xenobiotics and metabolites in a hepatic lobule. We conclude that heterogeneity in the biochemical and biophysical properties of xenobiotics combines with the complexity of blood flow in a lobule to create unique exposure patterns for hepatocytes in different lobular regions. Support or Funding Information This work was sponsored by National Institutes of Health/National Institute of General Medical Sciences grants R01 GM077138 and U01 GM111243.