title: Spatio-temporal simulation of first pass drug perfusion in the liver.
abstract: The liver is the central organ for detoxification of xenobiotics in the body. In pharmacokinetic modeling, hepatic metabolization capacity is typically quantified as hepatic clearance computed as degradation in well-stirred compartments. This is an accurate mechanistic description once a quasi-equilibrium between blood and surrounding tissue is established. However, this model structure cannot be used to simulate spatio-temporal distribution during the first instants after drug injection. In this paper, we introduce a new spatially resolved model to simulate first pass perfusion of compounds within the naive liver. The model is based on vascular structures obtained from computed tomography as well as physiologically based mass transfer descriptions obtained from pharmacokinetic modeling. The physiological architecture of hepatic tissue in our model is governed by both vascular geometry and the composition of the connecting hepatic tissue. In particular, we here consider locally distributed mass flow in liver tissue instead of considering well-stirred compartments. Experimentally, the model structure corresponds to an isolated perfused liver and provides an ideal platform to address first pass effects and questions of hepatic heterogeneity. The model was evaluated for three exemplary compounds covering key aspects of perfusion, distribution and metabolization within the liver. As pathophysiological states we considered the influence of steatosis and carbon tetrachloride-induced liver necrosis on total hepatic distribution and metabolic capacity. Notably, we found that our computational predictions are in qualitative agreement with previously published experimental data. The simulation results provide an unprecedented level of detail in compound concentration profiles during first pass perfusion, both spatio-temporally in liver tissue itself and temporally in the outflowing blood. We expect our model to be the foundation of further spatially resolved models of the liver in the future.
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: Markus
authors.initials: M
authors.lastname: Krauss
authors.affiliation: Computational Systems Biology, Bayer Technology Services, Leverkusen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Niederalt
authors.affiliation: Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gremse
authors.affiliation: Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Fraunhofer MEVIS, Bremen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schenk
authors.affiliation: Fraunhofer MEVIS, Bremen, Germany; School of Engineering and Science, Jacobs University, Bremen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Preusser
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
mesh_terms: D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D003287:Contrast Media / Q000737:chemistry; D005452:Fluoresceins / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008874:Midazolam / Q000493:pharmacokinetics*; D010477:Perfusion; D010539:Permeability; D062211:Spatio-Temporal Analysis; D015572:Spiramycin / Q000493:pharmacokinetics*; D013388:Succinimides / Q000493:pharmacokinetics*; D055114:X-Ray Microtomography / Q000379:methods; D015262:Xenobiotics / Q000493:pharmacokinetics
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D003287:Contrast Media; D005452:Fluoresceins; D013388:Succinimides; D015262:Xenobiotics; D015572:Spiramycin; D008874:Midazolam