Sluka2016 - Acetaminophen metabolism
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ABSTRACT:
Sluka2016 - Acetaminophen metabolism
Liver metabolism of Acetaminophen: Acetaminophen (APAP) is
metabolized in the liver in both Phase I and Phase II reactions.
Phase II reactions convert APAP to APAP-glucuronide and
APAP-sulfate. Phase I reactions involve Cytochrome P450 mediated
(mostly Cyp450-2E1 and -1A2) conversion of APAP to
N-acetyle-p-quinoneimine (NAPQI), which goes on to react with
cellular nucleophiles such as glutathione (GSH). At high doses of
APAP significant GSH depletion in hepatocyte occurs resulting in
cell necrosis and and in extreme cases death.
This model is described in the article:
A Liver-Centric Multiscale
Modeling Framework for Xenobiotics.
Sluka JP, Fu X, Swat M, Belmonte JM,
Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA.
PLoS ONE 2016; 11(9): e0162428
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.
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BIOMD0000000624.
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SUBMITTER: James P Sluka
PROVIDER: BIOMD0000000624 | BioModels | 2024-09-02
REPOSITORIES: BioModels
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