title: Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.
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.
authors.affiliation: Fraunhofer MEVIS, Bremen, Germany.
authors.forename: Lars Ole
authors.initials: LO
authors.lastname: Schwen
authors.affiliation: Computational Systems Biology, Bayer Technology Services, Leverkusen, Germany; Aachen Institute for Advanced Study in Computational Engineering Sciences, RWTH Aachen University, Aachen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Schenk
authors.affiliation: Freiburg Center for Data Analysis and Modeling (FDM), Institute of Physics, University of Freiburg, Freiburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kreutz
authors.affiliation: Freiburg Center for Data Analysis and Modeling (FDM), Institute of Physics, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: Clinic for Internal Medicine II/Molecular Biology, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: María Matilde
authors.initials: MM
authors.lastname: Bartolomé Rodríguez
authors.affiliation: Computational Systems Biology, Bayer Technology Services, Leverkusen, Germany; Institute of Applied Microbiology, RWTH Aachen University, Aachen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kuepfer
authors.affiliation: Fraunhofer MEVIS, Bremen, Germany; Jacobs University, Bremen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Preusser
mesh_terms: D000328:Adult; D000818:Animals; D001775:Blood Circulation; D002110:Caffeine / Q000493:pharmacokinetics; D005234:Fatty Liver / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000493:pharmacokinetics; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008954:Models, Biological; D010599:Pharmacokinetics; D012038:Regeneration
chemical_list: D007328:Insulin; D002110:Caffeine