A Liver-Centric Multiscale Modeling Framework for Xenobiotics.
We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that spa...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5026379?pdf=render |
| _version_ | 1818840145853415424 |
|---|---|
| author | James P Sluka Xiao Fu Maciej Swat Julio M Belmonte Alin Cosmanescu Sherry G Clendenon John F Wambaugh James A Glazier |
| author_facet | James P Sluka Xiao Fu Maciej Swat Julio M Belmonte Alin Cosmanescu Sherry G Clendenon John F Wambaugh James A Glazier |
| author_sort | James P Sluka |
| collection | DOAJ |
| description | We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics. |
| first_indexed | 2024-12-19T04:05:32Z |
| format | Article |
| id | doaj.art-16b20de816ff4c75b82958dcd34c4023 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T04:05:32Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-16b20de816ff4c75b82958dcd34c40232022-12-21T20:36:33ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01119e016242810.1371/journal.pone.0162428A Liver-Centric Multiscale Modeling Framework for Xenobiotics.James P SlukaXiao FuMaciej SwatJulio M BelmonteAlin CosmanescuSherry G ClendenonJohn F WambaughJames A GlazierWe describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.http://europepmc.org/articles/PMC5026379?pdf=render |
| spellingShingle | James P Sluka Xiao Fu Maciej Swat Julio M Belmonte Alin Cosmanescu Sherry G Clendenon John F Wambaugh James A Glazier A Liver-Centric Multiscale Modeling Framework for Xenobiotics. PLoS ONE |
| title | A Liver-Centric Multiscale Modeling Framework for Xenobiotics. |
| title_full | A Liver-Centric Multiscale Modeling Framework for Xenobiotics. |
| title_fullStr | A Liver-Centric Multiscale Modeling Framework for Xenobiotics. |
| title_full_unstemmed | A Liver-Centric Multiscale Modeling Framework for Xenobiotics. |
| title_short | A Liver-Centric Multiscale Modeling Framework for Xenobiotics. |
| title_sort | liver centric multiscale modeling framework for xenobiotics |
| url | http://europepmc.org/articles/PMC5026379?pdf=render |
| work_keys_str_mv | AT jamespsluka alivercentricmultiscalemodelingframeworkforxenobiotics AT xiaofu alivercentricmultiscalemodelingframeworkforxenobiotics AT maciejswat alivercentricmultiscalemodelingframeworkforxenobiotics AT juliombelmonte alivercentricmultiscalemodelingframeworkforxenobiotics AT alincosmanescu alivercentricmultiscalemodelingframeworkforxenobiotics AT sherrygclendenon alivercentricmultiscalemodelingframeworkforxenobiotics AT johnfwambaugh alivercentricmultiscalemodelingframeworkforxenobiotics AT jamesaglazier alivercentricmultiscalemodelingframeworkforxenobiotics AT jamespsluka livercentricmultiscalemodelingframeworkforxenobiotics AT xiaofu livercentricmultiscalemodelingframeworkforxenobiotics AT maciejswat livercentricmultiscalemodelingframeworkforxenobiotics AT juliombelmonte livercentricmultiscalemodelingframeworkforxenobiotics AT alincosmanescu livercentricmultiscalemodelingframeworkforxenobiotics AT sherrygclendenon livercentricmultiscalemodelingframeworkforxenobiotics AT johnfwambaugh livercentricmultiscalemodelingframeworkforxenobiotics AT jamesaglazier livercentricmultiscalemodelingframeworkforxenobiotics |