Multiscale modelling approach combining a kinetic model of glutathione metabolism with PBPK models of paracetamol and the potential glutathione-depletion biomarkers ophthalmic acid and 5-oxoproline in humans and rats

Geenen, Suzanne; Yates, James; Kenna, J. Gerry; Bois, Frédéric Y.; Wilson, Ian D.; Westerhoff, Hans V.

doi:10.1039/c3ib20245c

Cited by 38 publications

(25 citation statements)

References 39 publications

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“…As to the models themselves, their validity will probably be easier to check if they are generic and with a stable and well-documented structure [74]. This requirement, however, runs somewhat contrary to the next challenge: Coupling PBPK models to predictive pharmacology or toxicity models, both at the cellular level and at the organ level [75]. We hope however, that this stepby-step introduction to PBPK model development and simulation will help the reader in his/her first steps into that exciting area.…”

Section: Resultsmentioning

confidence: 91%

Modeling Pharmacokinetics

Brochot¹

2016

Methods in Molecular Biology

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Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software.

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Section: Resultsmentioning

confidence: 91%

Modeling Pharmacokinetics

Brochot¹

2016

Methods in Molecular Biology

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“…Therefore, we need additional information to be able to calibrate the intracellular APAP levels that are required in the system biology (SB) model. For that purpose, we used the results from a study using a physiologically based pharmacokinetic (PBPK) model coupled with an APAP metabolism system biology approach proposed by Geenen and collaborators (Geenen et al 2013). Following their results, we fixed a coefficient ratio of 3.6 between the intracellular and extracellular APAP concentration.…”

Section: Pharmacokinetic Modelmentioning

confidence: 99%

Investigation of acetaminophen toxicity in HepG2/C3a microscale cultures using a system biology model of glutathione depletion

et al. 2015

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We have integrated in vitro and in silico information to investigate acetaminophen (APAP) and its metabolite N-acetyl-p-benzoquinone imine (NAPQI) toxicity in liver biochip. In previous works, we observed higher cytotoxicity of HepG2/C3a cultivated in biochips when exposed to 1 mM of APAP for 72 h as compared to Petri cultures. We complete our investigation with the present in silico approach to extend the mechanistic interpretation of the intracellular kinetics of the toxicity process. For that purpose, we propose a mathematical model based on the coupling of a drug pharmacokinetic model (PK) with a systemic biology model (SB) describing the reactive oxygen species (ROS) production by NAPQI and the subsequent glutathione (GSH) depletion. The SB model was parameterized using (i) transcriptomic data, (ii) qualitative results of time lapses ROS fluorescent curves for both control and 1-mM APAP-treated experiments, and (iii) additional GSH literature data. The PK model was parameterized (i) using the in vitro kinetic data (at 160 μM, 1 mM, 10 mM), (ii) using the parameters resulting from a physiologically based pharmacokinetic (PBPK) literature model for APAP, and (iii) by literature data describing NAPQI formation. The PK-SB model predicted a ROS increase and GSH depletion due to the NAPQI formation. The transition from a detoxification phase and NAPQI and ROS accumulation was predicted for a NAPQI concentration ranging between 0.025 and 0.25 μM in the cytosol. In parallel, we performed a dose response analysis in biochips that shows a reduction of the final hepatic cell number appeared in agreement with the time and doses associated with the switch of the NAPQI detoxification/accumulation. As a result, we were able to correlate in vitro extracellular APAP exposures with an intracellular in silico ROS accumulation using an integration of a coupled mathematical and experimental liver on chip approach.

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“…Such extrapolations are required to define the dose of a drug or a toxic substance for use in humans when developing drugs or evaluating the safety of chemical products (Blaauboer, 2003). At the same time, mathematical models are useful for experimental studies and for developing new analytical systems as they can direct the choice of products and doses for testing, leading to rational optimization of the design of analytical systems (Geenen et al, 2013;GonS calves et al, 2013;Ierapetritou et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans

Prot

Maciel

Bricks

et al. 2014

Biotech & Bioengineering

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We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes.

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Multiscale modelling approach combining a kinetic model of glutathione metabolism with PBPK models of paracetamol and the potential glutathione-depletion biomarkers ophthalmic acid and 5-oxoproline in humans and rats

Abstract: Model equations:Equation for cytosolic glutamate (cglut) Equation for venous blood cysteine (bcys)

Cited by 38 publications

References 39 publications

Modeling Pharmacokinetics

Modeling Pharmacokinetics

Investigation of acetaminophen toxicity in HepG2/C3a microscale cultures using a system biology model of glutathione depletion

First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans

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