Science Inventory

A Liver-centric Multiscale Modeling Framework for Xenobiotics

Citation:

Sluka, J., X. Fu, M. Swat, J. Belmonte, A. Cosmanescu, S. Clendenon, J. Wambaugh, AND J. Glazier. A Liver-centric Multiscale Modeling Framework for Xenobiotics. PLoS ONE . Public Library of Science, San Francisco, CA, , 1-40, (2016).

Impact/Purpose:

Our study focuses on developing a multi-scale computational model to characterize both phase I and phase II metabolism of acetaminophen, by bridging Physiologically Based Pharmacokinetic (PBPK) modeling at the whole body level, cell movement and blood flow at the tissue level and cell signaling and drug metabolism at the sub-cellular level. This multiscale model bridges the CompuCell3D tool used by the Virtual Tissue project with the httk tool developed by the Rapid Exposure and Dosimetry project.

Description:

We describe a multi-scale framework for modeling acetaminophen-induced liver toxicity. Acetaminophen is a widely used analgesic. Overdose of acetaminophen can result in liver injury via its biotransformation into toxic product, which further induce massive necrosis. Our study focuses on developing a multi-scale computational model to characterize both phase I and phase II metabolism of acetaminophen, by bridging Physiologically Based Pharmacokinetic (PBPK) modeling at the whole body level, cell movement and blood flow at the tissue level and cell signaling and drug metabolism at the sub-cellular level. To validate the model, we estimated our model parameters by fi?tting serum concentrations of acetaminophen and its glucuronide and sulfate metabolites to experiments, and carried out sensitivity analysis on 35 parameters selected from three modules.

URLs/Downloads:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162428   Exit

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 09/16/2016
Record Last Revised: 11/09/2016
OMB Category: Other
Record ID: 331050

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY