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

PLoS Comput Biol. 2014 Mar 13;10(3):e1003499. doi: 10.1371/journal.pcbi.1003499. eCollection 2014 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Computer Simulation
  • Contrast Media / chemistry
  • Fluoresceins / pharmacokinetics*
  • Inactivation, Metabolic
  • Liver / drug effects*
  • Mice
  • Midazolam / pharmacokinetics*
  • Perfusion
  • Permeability
  • Spatio-Temporal Analysis
  • Spiramycin / pharmacokinetics*
  • Succinimides / pharmacokinetics*
  • X-Ray Microtomography / methods
  • Xenobiotics / pharmacokinetics

Substances

  • 5-(6)-carboxyfluorescein diacetate succinimidyl ester
  • Contrast Media
  • Fluoresceins
  • Succinimides
  • Xenobiotics
  • Spiramycin
  • Midazolam

Grant support

This work was funded by the German Ministry of Education and Research (BMBF) via the systems biology network Virtual Liver (http://www.virtual-liver.de/), grant numbers 0315743, 0315747, and 0315769. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.