A spatial-temporal model for zonal hepatotoxicity of acetaminophen

Means, Shawn; Ho, Harvey

doi:10.1016/j.dmpk.2018.09.266

Cited by 15 publications

(34 citation statements)

References 13 publications

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“…Our aim was to gain more insights into the observation that hepatocyte necrosis occurs earliest in the region closest to the central vein, resulting in zonal heterogeneity in hepatotoxicity. In order to perform these simulations, we have combined several mathematical methods, including a drug flow transport model and drug exchange model, an intracellular APAP metabolism model, and a model for the spatially varying distribution of CYP450 . This provides a novel platform that couples together the partial differential equation describing drug transport in sinusoids, with intracellular drug metabolism models (APAP in this case).…”

Section: Discussionmentioning

confidence: 99%

“… b S and b G are the rates of production, and d S and d G are the rates of natural decay of sulfate and GSH, respectively. We do not explicitly model APAP glucuronide (APAP‐G) or APAP sulfate (APAP‐S), but we do model the removal of APAP to form these compounds via the terms k G P i and k S S i P i in Equation , respectively …”

Section: Methodsmentioning

confidence: 99%

“…Previous mathematical models consider the spatial distribution of CYP450 only . Recently, our group has simulated the interplay of the spatial distributions of glucuronidation, sulfation, and oxidation enzymes on hepatotoxicity . We coupled an intracellular APAP metabolism model consisting of a system of ordinary differential equations (ODEs) with a spatial‐temporal sinusoid model and solved the system using the finite element method.…”

Section: Introductionmentioning

confidence: 99%

“…However, the model presented in Means and Ho did not include a drug transport equation and hence could not be used to investigate the impact of blood flow on hepatotoxicity. Nor did it feature an inhomogeneous GST distribution, while an overdose of APAP would deplete most (90%) of the GSH .…”

Section: Introductionmentioning

confidence: 99%

“…Nor did it feature an inhomogeneous GST distribution, while an overdose of APAP would deplete most (90%) of the GSH . The aim of this work is to develop a novel computational model that couples a drug transport model described by a one‐dimensional (1D) partial differential equation (PDE) with the subcellular APAP metabolism model used in Means and Ho to gain some insights into blood flow effects on hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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A computational model for hepatotoxicity by coupling drug transport and acetaminophen metabolism equations

Franiatte

Clarke

2019

Numer Methods Biomed Eng

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The spatial distributions of cytochrome P450 (CYP450) and glutathione (GSH) in liver lobules determine the heterogeneous hepatotoxicity of acetaminophen (APAP). Their interplay in conjunction with blood flow is not well understood. In this paper, we integrate a cellular APAP metabolism model with a sinusoidal blood flow to simulate the temporal‐spatial patterns of APAP‐induced hepatotoxicity. The heterogeneous distribution of CYP450 and GSH is modeled by linearly varying their reaction rates along the portal triad to the central vein axis of a sinusoid. We found that the spatial distribution of GSH, glutathione S‐transferases (GSTs), and CYP450 all contributes to the high acetaminophen protein adduct formation at zone 3 of the lobules. The reversed spatial gradients of CYP450 and GSH cause quick depletion of GSH, which is further accelerated by the distribution of GST. The hepatic flow congestion and hyperperfusion however do not seem to play a significant role in the zonal hepatotoxicity. The simulation results may be useful for understanding the APAP‐induced hepatotoxicity and associated pharmaceutical treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A computational model for hepatotoxicity by coupling drug transport and acetaminophen metabolism equations

Franiatte

Clarke

2019

Numer Methods Biomed Eng

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In silico modeling for the hepatic circulation and transport: From the liver organ to lobules

Means

Safaei

et al. 2022

WIREs Mechanisms of Disease

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The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro-hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies.These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state-of-the-art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project.

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