Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen.

This is a basic model of Acetaminophen (APAP, Paracetamol) pharmacokinetics in humans. Many of the model parameters (compartment volumes, volumetric flow rates, etc.) are scaled allometrically based on the body weight (BW) raised to the 3/4 power. Because of that, the assigned values of many of the parameters are recalculated at run time and are different than the default values for the particular entity (e.g., the volume of a compartment and the volumetric flow rate between compartments).

APAP dose is initially given in grams (APAP_Dose_gram), which is converted to moles via the APAP molecular weight (APAP_MW). APAP quantities throughout the rest of the models are given in moles.

The base parameters are for a 70Kg human and a pharmacological oral dose of 1.4 gram of APAP. Metabolism is modelled as a single ODE in the liver compartment and the metabolite does not leave that compartment.

This model is loosely based on the model of Wambaugh and Shaw (PLoS Comput Biol. 2010 Apr 22;6(4):e1000756. doi: 10.1371/journal.pcbi.1000756. Pubmed ID: PMID- 20421935) with the following changes:

The lung lumen compartment was omitted.
A kidney compartment was added.
Glomerular Filtration is from the kidney compartment.
The APAP dose was changed to 1.4g.
The gut adsorption rate constant (KGutabs), tissue partition coefficients and liver metabolism rate constant (CLmetabolism) were fit using the human in vivo data of Critchley (Critchley, J. A., Critchley, L. A. H., Anderson, P. J., and Tomlinson, B. 2005 Journal of clinical pharmacy and therapeutics, 30(2), 179-184).
To model the extensive re-adsorption of APAP from the kidney tubules back into the blood the QGfr value is modified. This was done by changing the scaling parameter QGFR_ref value from 0.31 to 0.039, resulting in a decrease in the QGfr value of 8 fold (from 7.2 L/hr to 0.91 L/hr).

The parameters in this file are the REFSIM parameters from our publication.

ORGANISM(S): Homo sapiens

SUBMITTER: Lucian Smith

PROVIDER: MODEL1509230010 | biostudies-other |

SECONDARY ACCESSION(S): 27636091

REPOSITORIES: biostudies-other

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Publications

A Liver-Centric Multiscale Modeling Framework for Xenobiotics.

Sluka James P JP Fu Xiao X Swat Maciej M Belmonte Julio M JM Cosmanescu Alin A Clendenon Sherry G SG Wambaugh John F JF Glazier James A JA

PloS one 20160916 9

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 metab ...[more]

PMID: 27636091

Publication: 1/2

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Project description:Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen. This is a basic model of Acetaminophen (APAP, Paracetamol) pharmacokinetics in humans. Many of the model parameters (compartment volumes, volumetric flow rates, etc.) are scaled allometrically based on the body weight (BW) raised to the 3/4 power. Because of that, the assigned values of many of the parameters are recalculated at run time and are different than the default values for the particular entity (e.g., the volume of a compartment and the volumetric flow rate between compartments). APAP dose is initially given in grams (APAP_Dose_gram), which is converted to moles via the APAP molecular weight (APAP_MW). APAP quantities throughout the rest of the models are given in moles. The base parameters are for a 70Kg human and a pharmacological oral dose of 1.4 gram of APAP. Metabolism is modelled as a single ODE in the liver compartment and the metabolite does not leave that compartment. This model is loosely based on the model of Wambaugh and Shaw (PLoS Comput Biol. 2010 Apr 22;6(4):e1000756. doi: 10.1371/journal.pcbi.1000756. Pubmed ID: PMID- 20421935) with the following changes: The lung lumen compartment was omitted. A kidney compartment was added. Glomerular Filtration is from the kidney compartment. The APAP dose was changed to 1.4g. The gut adsorption rate constant (KGutabs), tissue partition coefficients and liver metabolism rate constant (CLmetabolism) were fit using the human in vivo data of Critchley (Critchley, J. A., Critchley, L. A. H., Anderson, P. J., and Tomlinson, B. 2005 Journal of clinical pharmacy and therapeutics, 30(2), 179-184). To model the extensive re-adsorption of APAP from the kidney tubules back into the blood the QGfr value is modified. This was done by changing the scaling parameter QGFR_ref value from 0.31 to 0.039, resulting in a decrease in the QGfr value of 8 fold (from 7.2 L/hr to 0.91 L/hr). The parameters in this file are the REFSIM parameters from our publication.

Dataset Information

Sluka2016 - Acetaminophen PBPK

Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen.

Publications

A Liver-Centric Multiscale Modeling Framework for Xenobiotics.

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