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Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.

Schwen LO, Schenk A, Kreutz C, Timmer J, Bartolomé Rodríguez MM, Kuepfer L, Preusser T - PLoS ONE (2015)

Bottom Line: This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales.Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism.In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

View Article: PubMed Central - PubMed

Affiliation: Fraunhofer MEVIS, Bremen, Germany.

ABSTRACT
The mammalian liver plays a key role for metabolism and detoxification of xenobiotics in the body. The corresponding biochemical processes are typically subject to spatial variations at different length scales. Zonal enzyme expression along sinusoids leads to zonated metabolization already in the healthy state. Pathological states of the liver may involve liver cells affected in a zonated manner or heterogeneously across the whole organ. This spatial heterogeneity, however, cannot be described by most computational models which usually consider the liver as a homogeneous, well-stirred organ. The goal of this article is to present a methodology to extend whole-body pharmacokinetics models by a detailed liver model, combining different modeling approaches from the literature. This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales. Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism. To show that this approach is generally applicable for different physiological processes, we show three applications as proofs of concept, covering a range of species, compounds, and diseased states: clearance of midazolam in steatotic human livers, clearance of caffeine in mouse livers regenerating from necrosis, and a parameter study on the impact of different cell entities on insulin uptake in mouse livers. The examples illustrate how variations only discernible at the local scale influence substance distribution in the plasma at the whole-body level. In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

No MeSH data available.


Related in: MedlinePlus

Human Liver Vascular Dataset.The image shows a visualization of a human liver shape including algorithmically refined vascular structures. The supplying vascular system, comprising portal vein and hepatic artery, is shown in red, the draining vascular system (hepatic vein) in blue.
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pone.0133653.g003: Human Liver Vascular Dataset.The image shows a visualization of a human liver shape including algorithmically refined vascular structures. The supplying vascular system, comprising portal vein and hepatic artery, is shown in red, the draining vascular system (hepatic vein) in blue.

Mentions: The table gives an overview of the processes being modeled and the numerical techniques applied in each of the model building blocks for the distinct spatial scales, cf. Fig 2. The overall model requires an integration of submodels of different dimensionality: from 0D, referring to models where spatial effects are not explicitly considered, via 1D sinusoids to a 3D organ. Round brackets in the table refer to equations in this article, square brackets to literature.


Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.

Schwen LO, Schenk A, Kreutz C, Timmer J, Bartolomé Rodríguez MM, Kuepfer L, Preusser T - PLoS ONE (2015)

Human Liver Vascular Dataset.The image shows a visualization of a human liver shape including algorithmically refined vascular structures. The supplying vascular system, comprising portal vein and hepatic artery, is shown in red, the draining vascular system (hepatic vein) in blue.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519332&req=5

pone.0133653.g003: Human Liver Vascular Dataset.The image shows a visualization of a human liver shape including algorithmically refined vascular structures. The supplying vascular system, comprising portal vein and hepatic artery, is shown in red, the draining vascular system (hepatic vein) in blue.
Mentions: The table gives an overview of the processes being modeled and the numerical techniques applied in each of the model building blocks for the distinct spatial scales, cf. Fig 2. The overall model requires an integration of submodels of different dimensionality: from 0D, referring to models where spatial effects are not explicitly considered, via 1D sinusoids to a 3D organ. Round brackets in the table refer to equations in this article, square brackets to literature.

Bottom Line: This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales.Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism.In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

View Article: PubMed Central - PubMed

Affiliation: Fraunhofer MEVIS, Bremen, Germany.

ABSTRACT
The mammalian liver plays a key role for metabolism and detoxification of xenobiotics in the body. The corresponding biochemical processes are typically subject to spatial variations at different length scales. Zonal enzyme expression along sinusoids leads to zonated metabolization already in the healthy state. Pathological states of the liver may involve liver cells affected in a zonated manner or heterogeneously across the whole organ. This spatial heterogeneity, however, cannot be described by most computational models which usually consider the liver as a homogeneous, well-stirred organ. The goal of this article is to present a methodology to extend whole-body pharmacokinetics models by a detailed liver model, combining different modeling approaches from the literature. This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales. Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism. To show that this approach is generally applicable for different physiological processes, we show three applications as proofs of concept, covering a range of species, compounds, and diseased states: clearance of midazolam in steatotic human livers, clearance of caffeine in mouse livers regenerating from necrosis, and a parameter study on the impact of different cell entities on insulin uptake in mouse livers. The examples illustrate how variations only discernible at the local scale influence substance distribution in the plasma at the whole-body level. In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

No MeSH data available.


Related in: MedlinePlus