Spatio-Temporal Simulation of First Pass Drug Perfusion in the Liver

Lars Ole Schwen, Markus Krauss, Christoph Niederalt, Felix Gremse, Fabian Kiessling, Andrea Schenk, Tobias Preusser and Lars Kuepfer

PLOS Computational Biology, 2014, vol. 10, issue 3, 1-18

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.Author Summary: The liver continuously removes xenobiotic compounds from the blood in the mammalian body. Most computational models represent the liver as composed of few well-stirred subcompartments so that a spatially resolved simulation of hepatic perfusion and compound distribution right after drug administration is currently not available. To mechanistically describe the local distribution of compounds in liver tissue during first pass perfusion, we here present a computational model which combines micro-CT based vascular structures with mass transfer descriptions used in physiologically based pharmacokinetic modeling. In the resulting spatio-temporal model, hepatic mass transfer is governed by the physiological architecture and the composition of the connecting hepatic tissue, such that hepatic heterogeneity and spatial distribution can be described mechanistically. The performance of our model is shown for exemplary compounds addressing key aspects of distribution and metabolization of drugs within a mouse liver. We furthermore investigate the impact of steatosis and carbon tetrachloride-induced liver necrosis. Notably, we find that our computational predictions are in qualitative agreement with previous experimental results in animal models. In the future, our spatially resolved model will be extended by including additional physiological information and by taking into account recirculation through the body.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003499

DOI: 10.1371/journal.pcbi.1003499

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