title: A Liver-Centric Multiscale Modeling Framework for Xenobiotics.
abstract: 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.
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: James P
authors.identifier: http://orcid.org/0000-0002-5901-1404
authors.initials: JP
authors.lastname: Sluka
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: Xiao
authors.identifier: http://orcid.org/0000-0002-8611-891X
authors.initials: X
authors.lastname: Fu
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: Maciej
authors.initials: M
authors.lastname: Swat
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: Julio M
authors.identifier: http://orcid.org/0000-0002-4315-9631
authors.initials: JM
authors.lastname: Belmonte
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: Alin
authors.initials: A
authors.lastname: Cosmanescu
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: Sherry G
authors.initials: SG
authors.lastname: Clendenon
authors.affiliation: National Center for Computational Toxicology Office of Research and Development US EPA, Research Triangle Park, NC 27711, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Wambaugh
authors.affiliation: Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Glazier
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008962:Models, Theoretical; D011381:Programming Languages; D015262:Xenobiotics
chemical_list: D015262:Xenobiotics; D000082:Acetaminophen