Dataset Information

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.

SUBMITTER: Schwen LO

PROVIDER: S-EPMC3952820 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Spatio-temporal simulation of first pass drug perfusion in the liver.

Schwen Lars Ole LO Krauss Markus M Niederalt Christoph C Gremse Felix F Kiessling Fabian F Schenk Andrea A Preusser Tobias T Kuepfer Lars L

PLoS computational biology 20140313 3

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 thi ...[more]

PMID: 24625393

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Project description:BackgroundRecently, the availability of high-resolution microscopy together with the advancements in the development of biomarkers as reporters of biomolecular interactions increased the importance of imaging methods in molecular cell biology. These techniques enable the investigation of cellular characteristics like volume, size and geometry as well as volume and geometry of intracellular compartments, and the amount of existing proteins in a spatially resolved manner. Such detailed investigations opened up many new areas of research in the study of spatial, complex and dynamic cellular systems. One of the crucial challenges for the study of such systems is the design of a well stuctured and optimized workflow to provide a systematic and efficient hypothesis verification. Computer Science can efficiently address this task by providing software that facilitates handling, analysis, and evaluation of biological data to the benefit of experimenters and modelers.ResultsThe Spatio-Temporal Simulation Environment (STSE) is a set of open-source tools provided to conduct spatio-temporal simulations in discrete structures based on microscopy images. The framework contains modules to digitize, represent, analyze, and mathematically model spatial distributions of biochemical species. Graphical user interface (GUI) tools provided with the software enable meshing of the simulation space based on the Voronoi concept. In addition, it supports to automatically acquire spatial information to the mesh from the images based on pixel luminosity (e.g. corresponding to molecular levels from microscopy images). STSE is freely available either as a stand-alone version or included in the linux live distribution Systems Biology Operational Software (SB.OS) and can be downloaded from http://www.stse-software.org/. The Python source code as well as a comprehensive user manual and video tutorials are also offered to the research community. We discuss main concepts of the STSE design and workflow. We demonstrate it's usefulness using the example of a signaling cascade leading to formation of a morphological gradient of Fus3 within the cytoplasm of the mating yeast cell Saccharomyces cerevisiae.ConclusionsSTSE is an efficient and powerful novel platform, designed for computational handling and evaluation of microscopic images. It allows for an uninterrupted workflow including digitization, representation, analysis, and mathematical modeling. By providing the means to relate the simulation to the image data it allows for systematic, image driven model validation or rejection. STSE can be scripted and extended using the Python language. STSE should be considered rather as an API together with workflow guidelines and a collection of GUI tools than a stand alone application. The priority of the project is to provide an easy and intuitive way of extending and customizing software using the Python language.

Project description:PURPOSE:To present and assess an automatic nonrigid image registration framework that compensates motion in cardiac magnetic resonance imaging (MRI) perfusion series and auxiliary images acquired under a wide range of conditions to facilitate myocardial perfusion quantification. MATERIALS AND METHODS:Our framework combines discrete feature matching for large displacement estimation with a dense variational optical flow formulation in a multithreaded architecture. This framework was evaluated on 291 clinical subjects to register 1.5T and 3.0T steady-state free-precession (FISP) and fast low-angle shot (FLASH) dynamic contrast myocardial perfusion images, arterial input function (AIF) images, and proton density (PD)-weighted images acquired under breath-hold (BH) and free-breath (FB) settings. RESULTS:Our method significantly improved frame-to-frame appearance consistency compared to raw series, expressed in correlation coefficient (R2 ?=?0.996?±?3.735E-3 vs. 0.978?±?2.024E-2, P < 0.0001) and mutual information (3.823?±?4.098E-1 vs. 2.967?±?4.697E-1, P < 0.0001). It is applicable to both BH (R2 ?=?0.998?±?3.217E-3 vs. 0.990?±?7.527E-3) and FB (R2 ?=?0.995?±?3.410E-3 vs. 0.968?±?2.257E-3) paradigms as well as FISP and FLASH sequences. The method registers PD images to perfusion T1 series (9.70% max increase in R2 vs. no registration, P < 0.001) and also corrects motion in low-resolution AIF series (R2 ?=?0.987?±?1.180E-2 vs. 0.964?±?3.860E-2, P < 0.001). Finally, we showed the myocardial perfusion contrast dynamic was preserved in the motion-corrected images compared to the raw series (R2 ?=?0.995?±?6.420E-3). CONCLUSION:The critical step of motion correction prior to pixel-wise cardiac MR perfusion quantification can be performed with the proposed universal system. It is applicable to a wide range of perfusion series and auxiliary images with different acquisition settings. LEVEL OF EVIDENCE:3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1060-1072.

Dataset Information

Spatio-temporal simulation of first pass drug perfusion in the liver.

Publications

Spatio-temporal simulation of first pass drug perfusion in the liver.

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