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Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models

Xiao Fu, James P. Sluka, Sherry G. Clendenon, Kenneth W. Dunn, Zemin Wang, James E. Klaunig, James A. Glazier, Olivier Barbier
2018 PLoS ONE  
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.  ...  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  ...  We constructed a virtual mouse liver lobule (Fig 3B and 3C ) based on the analysis of rodent liver lobules by us ( Fig 3A and Section 1.2 in S1 Text) and others [25] .  ... 
doi:10.1371/journal.pone.0198060 pmid:30212461 pmcid:PMC6136710 fatcat:axllu42gyzgu5d427szhlgvajy

A Liver-Centric Multiscale Modeling Framework for Xenobiotics

James P. Sluka, Xiao Fu, Maciej Swat, Julio M. Belmonte, Alin Cosmanescu, Sherry G. Clendenon, John F. Wambaugh, James A. Glazier, Edward E Schmidt
2016 PLoS ONE  
We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism.  ...  A model of APAP metabolism that treats the liver as a "well stirred" compartment may miss or underestimate the heterogeneity of the liver's responses.  ...  We thank the entire SBML community for the development of standards, tools and simulators that greatly facilitate the creation of annotated and reusable ODE based models.  ... 
doi:10.1371/journal.pone.0162428 pmid:27636091 pmcid:PMC5026379 fatcat:uow7debu5bdo5b7dkukqzwxmcm

Tissue-Level Modeling of Xenobiotic Metabolism in Liver: An Emerging Tool for Enabling Clinical Translational Research

Marianthi G. Lerapetritou, Panos G. Georgopoulos, Charles M. Roth, Loannis P. Androulakis
2009 Clinical and Translational Science  
a rapidly evolving knowledge base for a "systems biology of the liver."  ...  these models in the quest of rationalizing the process of evaluating drug efficacy and toxicity.  ...  This work has not been reviewed by and does not represent the opinions of the funding agencies.  ... 
doi:10.1111/j.1752-8062.2009.00092.x pmid:20443896 pmcid:PMC3068531 fatcat:zcbnw2xex5aw3ihuujmuv2xb2q

Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

Sudin Bhattacharya, Lisl K.M. Shoda, Qiang Zhang, Courtney G. Woods, Brett A. Howell, Scott Q. Siler, Jeffrey L. Woodhead, Yuching Yang, Patrick McMullen, Paul B. Watkins, Melvin E. Andersen
2012 Frontiers in Physiology  
One approach involves development of a spatial, multicellular "virtual tissue" model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated  ...  Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety  ...  members of the DILI-sim Initiative (www.dilisym.com).  ... 
doi:10.3389/fphys.2012.00462 pmid:23248599 pmcid:PMC3522076 fatcat:o5oumw2qajeipgyo4ehyfyys3u

Physiologically Based Synthetic Models of Hepatic Disposition

C. Anthony Hunt, Glen E. P. Ropella, Li Yan, Daniel Y. Hung, Michael S. Roberts
2006 Journal of Pharmacokinetics and Pharmacodynamics  
It relies on object-oriented programming A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue  ...  We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation.  ...  CAH thanks Amina Qutub for her early efforts in agent-based modeling.  ... 
doi:10.1007/s10928-006-9031-3 pmid:17051440 fatcat:d7p2scuw2ve6ld45jd6itomuf4

A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models

Vahid Rezania, Rebeccah Marsh, Dennis Coombe, Jack Tuszynski
2013 Theoretical Biology and Medical Modelling  
We extend a physiologically-based lattice model for the transport and metabolism of drugs in the liver lobule (liver functional unit) to consider structural and spatial variability.  ...  These conclusions are based on the dominant role of convection in well-vascularized tissue with a given structure.  ...  The Allard Foundation and the Alberta Advanced Education and Technology.  ... 
doi:10.1186/1742-4682-10-53 pmid:24007357 pmcid:PMC3833673 fatcat:tmvs6vlhxnhsvphtlrxxpu56gy

A small-scale anatomical dosimetry model of the liver

Anna Stenvall, Erik Larsson, Sven-Erik Strand, Bo-Anders Jönsson
2014 Physics in Medicine and Biology  
Material and method: The mathematical model created, based on the microstructure of the hepatic lobule, is used to calculate absorbed doses on a tissue level for different radionuclides and for different  ...  In this work we developed a small-scale dosimetry model of the liver, for Monte Carlo calculations of detailed and more accurate absorbed dose distributions of the liver microstructure.  ...  of this project and for their never-ending source of new approaches and ideas concerning the model making and its usage.  ... 
doi:10.1088/0031-9155/59/13/3353 pmid:24874832 fatcat:33jsglundnb3dlfx425u4yu62i

Falsifying an Enzyme Induction Mechanism within a Validated, Multiscale Liver Model

Glen E. P. Ropella, Ryan C. Kennedy, C. Anthony Hunt
2012 International journal of agent technologies and systems  
The focus is an In Silico Liver (ISL) model family and an evolving suite of mechanistic hypotheses about (rat) liver-drug interactions. ISLs are multiscale and hierarchical.  ...  We demonstrate a multi-scalar validation/falsification event in which we validate the mechanism against coarse grain measures of liver perfusate drug levels and falsify it against a medium grained measure  ...  on studying the computational construct, the simulation itself.  ... 
doi:10.4018/jats.2012070101 fatcat:sl6t6urckjgpzcnkgh2vhi2ztm

Physics-based tissue simulator to model multicellular systems: A study of liver regeneration and hepatocellular carcinoma recurrence [article]

Luciana Melina Luque, Carlos Manuel Carlevaro, Camilo Llamoza Torres, Enrique Lomba
2022 arXiv   pre-print
We present a multiagent-based model that captures the interactions between different types of cells with their microenvironment, and enables the analysis of the emergent global behavior during tissue regeneration  ...  By correlating these spatial characteristics with in silico treatment results, the model provides a framework to assess treatment combinations in different scenarios based on patient-specific experimental  ...  Simulation CPU time depends on model parameters such as domain (lattice) size, cell number and simulation length (in time); a typical simulation run takes approximately 6 h on a single core of an Intel  ... 
arXiv:2202.03512v1 fatcat:jwiuojmto5dj5n5rnx3nfw5u2y

Simulating Microdosimetry in a Virtual Hepatic Lobule

John Wambaugh, Imran Shah, Daniel A. Beard
2010 PLoS Computational Biology  
Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule.  ...  Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule.  ...  Author Contributions Conceived and designed the experiments: JW IS. Performed the experiments: JW. Analyzed the data: JW. Contributed reagents/materials/analysis tools: JW. Wrote the paper: JW IS.  ... 
doi:10.1371/journal.pcbi.1000756 pmid:20421935 pmcid:PMC2858695 fatcat:byxx4aed6zetlbjiso6z3b3jiy

A quantitative high-resolution computational mechanics cell model for growing and regenerating tissues

Paul Van Liedekerke, Johannes Neitsch, Tim Johann, Enrico Warmt, Ismael Gonzàlez-Valverde, Stefan Hoehme, Steffen Grosser, Josef Kaes, Dirk Drasdo
2019 Biomechanics and Modeling in Mechanobiology  
We present a 3D high-resolution cell-based model integrating information from measurements in order to obtain a refined and quantitative understanding of the impact of cell-biomechanical effects on the  ...  to exert on its environment to close a tissue lesion, is much smaller than predicted by center-based models.  ...  Green lines outline a liver lobule substructure in the tissue. b Structure of the blood vessel network of a single lobule within the model. c Part of the network used for the simulations with the DCM.  ... 
doi:10.1007/s10237-019-01204-7 pmid:31749071 pmcid:PMC7005086 fatcat:tycd6wlhr5c4fjawu7ueog6soe

At the Biological Modeling and Simulation Frontier

C. Anthony Hunt, Glen E. P. Ropella, Tai Ning Lam, Jonathan Tang, Sean H. J. Kim, Jesse A. Engelberg, Shahab Sheikh-Bahaei
2009 Pharmaceutical Research  
We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods.  ...  Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena  ...  An ISL represents a liver as a large, parallel collection of similar lobules (Fig. 7A ). An ISL's functional unit is the same as the liver's: a lobule.  ... 
doi:10.1007/s11095-009-9958-3 pmid:19756975 pmcid:PMC2763179 fatcat:rq6ve35b5vgebmd3orvzutmam4

Data-driven modelling of biological multi-scale processes [article]

Jan Hasenauer, Nick Jagiella, Sabrina Hross, Fabian J. Theis
2015 arXiv   pre-print
Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes.  ...  A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales.  ...  Union within the ERC grant "LatentCauses", and the Postdoctoral Fellowship Program (PFP) of the Helmholtz Zentrum München.  ... 
arXiv:1506.06392v1 fatcat:borcu4q7nbcodp6kdpvryswl7i

Biomimetic in Silico Devices [chapter]

C. Anthony Hunt, Glen E. P. Ropella, Michael S. Roberts, Li Yan
2005 Lecture Notes in Computer Science  
In this report we focus on the liver; the goal is to validate components that mimic features of the lobule (the hepatic primary functional unit) and dynamic aspects of liver behavior, structure, and function  ...  An assembly of lobule-mimetic devices represents an in silico liver. We validate against outflow profiles for sucrose administered as a bolus to isolated, perfused rat livers.  ...  Device Design Modeling Approach and Biological Data Rather than the traditional inductive, analytic modeling approach, we used a constructive approach based in part on ideas and concepts from several  ... 
doi:10.1007/978-3-540-25974-9_4 fatcat:nyxuvb6apfds7ovd7wvllznxxe

Modeling and Simulation of Hepatic Drug Disposition Using a Physiologically Based, Multi-agent In Silico Liver

Li Yan, Glen E. P. Ropella, Sunwoo Park, Michael S. Roberts, C. Anthony Hunt
2007 Pharmaceutical Research  
Validate a physiologically based, mechanistic, in silico liver (ISL) for studying the hepatic disposition and metabolism of antipyrine, atenolol, labetalol, diltiazem, and sucrose administered alone or  ...  The consequences of ISL parameter changes on outflow profiles were explored.  ...  The work was abstracted in part from the PhD dissertation Modeling and Simulation of Hepatic Drug Disposition presented by LY to the Graduate Division, University of California, Berkeley, CA.  ... 
doi:10.1007/s11095-007-9494-y pmid:18044012 fatcat:qhn2ca6i6jda7lx65ybsrhlzem
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