Limits...
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

Caffeine Clearance After CCl4-Induced Necrosis.The plot shows the caffeine concentrations in the plasma in the venous blood pool for 24 hours after intravenous bolus injection at different time points during the necrosis development and regeneration process induced by CCl4. The influence of the necrotic damage occurred during day 0, leading to slowest decrease of caffeine concentration in the venous blood for the injection at day 1. Regeneration during days 1 to 7, according to our necrosis model from Fig 6, lead to increasingly faster decrease of the caffeine concentrations for the later injections, until the fully regenerated state was reached for the injection at day 7. The inset shows the second pass after the first recirculation cycle, in this case after 30.2 s. The table lists the half-life of caffeine in the organism, i.e., the first decrease by 50%, if it occurs within one day after the administration. These numbers confirm the observations from the plot which only involves the venous blood pool.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4519332&req=5

pone.0133653.g010: Caffeine Clearance After CCl4-Induced Necrosis.The plot shows the caffeine concentrations in the plasma in the venous blood pool for 24 hours after intravenous bolus injection at different time points during the necrosis development and regeneration process induced by CCl4. The influence of the necrotic damage occurred during day 0, leading to slowest decrease of caffeine concentration in the venous blood for the injection at day 1. Regeneration during days 1 to 7, according to our necrosis model from Fig 6, lead to increasingly faster decrease of the caffeine concentrations for the later injections, until the fully regenerated state was reached for the injection at day 7. The inset shows the second pass after the first recirculation cycle, in this case after 30.2 s. The table lists the half-life of caffeine in the organism, i.e., the first decrease by 50%, if it occurs within one day after the administration. These numbers confirm the observations from the plot which only involves the venous blood pool.

Mentions: The caffeine concentrations in the plasma in the venous blood pool show a second and weak third peak after about 30 and 60 seconds, see the small line plot in Fig 10. Later peaks are of diminishing amplitude and not visible in the curves. These recurring peaks are superpositions of the delays due to the liver model and the recirculation as well as an exchange between subcompartments of all organs, the spatially resolved liver and the well-stirred remaining organs. The peaks thus take longer than the total recirculation time for mice of τrec total = 19.72 s, see the discussion of the recirculation time scale in the human midazolam case above. This effect qualitatively occured regardless of the necrotic state of the model. On the longer time scale of one day, the necrotic state of the model had a major influence, see large line plot in Fig 10: for injection at day 0, the necrosis developed and slowed down the decrease of caffeine concentration in the plasma in the venous blood pool. For injection at day 1, the slowest concentration decrease can be observed. Regeneration lead to an increasingly larger metabolizing region for the injections at days 2 to 7, leading to faster decrease of the caffeine concentrations, until the fully regenerated state was reached for the injection at day 7.


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)

Caffeine Clearance After CCl4-Induced Necrosis.The plot shows the caffeine concentrations in the plasma in the venous blood pool for 24 hours after intravenous bolus injection at different time points during the necrosis development and regeneration process induced by CCl4. The influence of the necrotic damage occurred during day 0, leading to slowest decrease of caffeine concentration in the venous blood for the injection at day 1. Regeneration during days 1 to 7, according to our necrosis model from Fig 6, lead to increasingly faster decrease of the caffeine concentrations for the later injections, until the fully regenerated state was reached for the injection at day 7. The inset shows the second pass after the first recirculation cycle, in this case after 30.2 s. The table lists the half-life of caffeine in the organism, i.e., the first decrease by 50%, if it occurs within one day after the administration. These numbers confirm the observations from the plot which only involves the venous blood pool.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133653.g010: Caffeine Clearance After CCl4-Induced Necrosis.The plot shows the caffeine concentrations in the plasma in the venous blood pool for 24 hours after intravenous bolus injection at different time points during the necrosis development and regeneration process induced by CCl4. The influence of the necrotic damage occurred during day 0, leading to slowest decrease of caffeine concentration in the venous blood for the injection at day 1. Regeneration during days 1 to 7, according to our necrosis model from Fig 6, lead to increasingly faster decrease of the caffeine concentrations for the later injections, until the fully regenerated state was reached for the injection at day 7. The inset shows the second pass after the first recirculation cycle, in this case after 30.2 s. The table lists the half-life of caffeine in the organism, i.e., the first decrease by 50%, if it occurs within one day after the administration. These numbers confirm the observations from the plot which only involves the venous blood pool.
Mentions: The caffeine concentrations in the plasma in the venous blood pool show a second and weak third peak after about 30 and 60 seconds, see the small line plot in Fig 10. Later peaks are of diminishing amplitude and not visible in the curves. These recurring peaks are superpositions of the delays due to the liver model and the recirculation as well as an exchange between subcompartments of all organs, the spatially resolved liver and the well-stirred remaining organs. The peaks thus take longer than the total recirculation time for mice of τrec total = 19.72 s, see the discussion of the recirculation time scale in the human midazolam case above. This effect qualitatively occured regardless of the necrotic state of the model. On the longer time scale of one day, the necrotic state of the model had a major influence, see large line plot in Fig 10: for injection at day 0, the necrosis developed and slowed down the decrease of caffeine concentration in the plasma in the venous blood pool. For injection at day 1, the slowest concentration decrease can be observed. Regeneration lead to an increasingly larger metabolizing region for the injections at days 2 to 7, leading to faster decrease of the caffeine concentrations, until the fully regenerated state was reached for the injection at day 7.

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