Risk Assessment Specialty Section (RASS) with the Biological Modeling Specialty Section (BMSS) 2017 Fall Season Webinar

Wednesday, December 13, 3:00pm—4:30pm (EST)

A Liver-centric Multiscale Modeling Framework for Xenobiotics

James Sluka, PhD, Biocomplexity Institute, Indiana University

Abstract: We present a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We will focus on a computational model that characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. The model incorporates sub-models at three scales; (1) Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, (2) cell and blood flow modeling at the tissue/organ level and (3) metabolism, both Phase I and Phase II, at the sub-cellular level. We 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 allows us to include 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 carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation in the sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose multi-scale pharmacokinetic model for xenobiotics. The URL for the PlosOne open access journal article of the work is here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162428