Full Paper

A physiologically based pharmacokinetic model of vascular–extravascular exchanges during liver carcinogenesis: application to MRI contrast agents

  1. Muriel Mescam1,2,*,
  2. Pierre-Antoine Eliat3,
  3. Claire Fauvel1,2,3,
  4. Jacques D. de Certaines3,4,
  5. Johanne Bézy-Wendling1,2

Article first published online: 14 SEP 2007

DOI: 10.1002/cmmi.147

Issue

Contrast Media & Molecular Imaging

Contrast Media & Molecular Imaging

Volume 2, Issue 5, pages 215–228, September/October 2007

Additional Information

How to Cite

Mescam, M., Eliat, P.-A., Fauvel, C., Certaines, J. D. d. and Bézy-Wendling, J. (2007), A physiologically based pharmacokinetic model of vascular–extravascular exchanges during liver carcinogenesis: application to MRI contrast agents. Contrast Media Mol Imaging, 2: 215–228. doi: 10.1002/cmmi.147

Author Information

  1. 1

    INSERM, U642, Rennes, F-35000, France

  2. 2

    Université de Rennes 1, LTSI, Rennes, F-35000, France

  3. 3

    PRISM, ImagiVeC UPRES-EA 3890, IFR 140 GFAS, OUEST-génopole®, Faculté de Médecine, Université de Rennes 1, Rennes, France

  4. 4

    Centre Eugène Marquis, Département de Biologie, Rennes, France

*LTSI, Campus de Beaulieu, Université de Rennes 1, 263 Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France.

Publication History

  1. Issue published online: 20 DEC 2007
  2. Article first published online: 14 SEP 2007
  3. Manuscript Accepted: 5 AUG 2007
  4. Manuscript Revised: 23 JUL 2007
  5. Manuscript Received: 2 MAR 2007

Funded by

  • Region Bretagne OUEST-genopole®

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Keywords:

  • PBPK model;
  • molecule transport;
  • liver microvascularization;
  • contrast agent;
  • cancer;
  • hepato-cellular carcinoma;
  • MRI;
  • simulation

Abstract

The extraction of physiological parameters by non-invasive imaging techniques such as dynamic magnetic resonance imaging (MRI) or positron emission tomography requires a knowledge of molecular distribution and exchange between microvascularization and extravascular tissues. These phenomena not only depend on the physicochemical characteristics of the injected molecules but also the pathophysiological state of the targeted organ. We developed a five-compartment physiologically based pharmacokinetic model focused on hepatic carcinogenesis and MRI contrast agents. This model includes physical characteristics of the contrast agent, dual specific liver supply, microvessel wall properties and transport parameters that are compatible with hepatocarcinoma development. The evolution of concentrations in the five compartments showed significant differences in the distribution of three molecules (differentiated by their diameters and diffusion coefficients ranging, respectively, from 0.9 to 62 nm and from 68.10−9 to 47.10−7 cm2 s−1) in simulated regeneration nodules and dysplastic nodules, as well as in medium- and poorly differentiated hepatocarcinoma. These results are in agreement with known vascular modifications such as arterialization that occur during hepatocarcinogenesis. This model can be used to study the pharmacokinetics of contrast agents and consequently to extract parameters that are characteristic of the tumor development (like permeability), after fitting simulated to in vivo data. Copyright © 2007 John Wiley & Sons, Ltd.

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