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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

Organ-Scale Midazolam Concentration Profiles.For an assumed infusion of midazolam into the portal vein within 5 seconds, and our human whole-body model with a liver described by 10 000 representative sinusoids, the plot shows the midazolam concentrations in the blood plasma flowing out of the liver. In these model predictions, the different steatotic cases lead to differences during the first minutes. Afterwards, only the healthy state leads to concentrations distinct from the steatotic cases.
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pone.0133653.g009: Organ-Scale Midazolam Concentration Profiles.For an assumed infusion of midazolam into the portal vein within 5 seconds, and our human whole-body model with a liver described by 10 000 representative sinusoids, the plot shows the midazolam concentrations in the blood plasma flowing out of the liver. In these model predictions, the different steatotic cases lead to differences during the first minutes. Afterwards, only the healthy state leads to concentrations distinct from the steatotic cases.

Mentions: In Fig 9, differences between the three steatotic states during the first minutes can be observed. This shows a key property of our spatially resolved model which is capable of distinguishing different spatial patterns with the same total steatotic lipid accumulation. In these liver outflow curves, two concentration maxima can be observed. The first peak corresponds to the first pass after the blood flow transit time of the organ, which is the same for all four cases. The second peak corresponds to the different apparent peak velocities for the four cases observed in Fig 8. This shows that the effect of different apparent peak velocities is also present in the superposition of 10 000 different steatosis patterns of the four types (healthy, predominantly periportal, predominantly pericentral, non-zonal) and in particular not an artifact of the specific single patterns used for the simulations shown in Fig 8.


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)

Organ-Scale Midazolam Concentration Profiles.For an assumed infusion of midazolam into the portal vein within 5 seconds, and our human whole-body model with a liver described by 10 000 representative sinusoids, the plot shows the midazolam concentrations in the blood plasma flowing out of the liver. In these model predictions, the different steatotic cases lead to differences during the first minutes. Afterwards, only the healthy state leads to concentrations distinct from the steatotic cases.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133653.g009: Organ-Scale Midazolam Concentration Profiles.For an assumed infusion of midazolam into the portal vein within 5 seconds, and our human whole-body model with a liver described by 10 000 representative sinusoids, the plot shows the midazolam concentrations in the blood plasma flowing out of the liver. In these model predictions, the different steatotic cases lead to differences during the first minutes. Afterwards, only the healthy state leads to concentrations distinct from the steatotic cases.
Mentions: In Fig 9, differences between the three steatotic states during the first minutes can be observed. This shows a key property of our spatially resolved model which is capable of distinguishing different spatial patterns with the same total steatotic lipid accumulation. In these liver outflow curves, two concentration maxima can be observed. The first peak corresponds to the first pass after the blood flow transit time of the organ, which is the same for all four cases. The second peak corresponds to the different apparent peak velocities for the four cases observed in Fig 8. This shows that the effect of different apparent peak velocities is also present in the superposition of 10 000 different steatosis patterns of the four types (healthy, predominantly periportal, predominantly pericentral, non-zonal) and in particular not an artifact of the specific single patterns used for the simulations shown in Fig 8.

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