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ToxSci Advance Access published online on April 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn080
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR INTRAVENOUS AND INGESTED DIMETHYLARSINIC ACID (DMAV) IN MICE.

Marina V. Evans, Sean M. Dowd, Elaina M. Kenyon, Michael F. Hughes and Hisham A. El-Masri

National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711

Corresponding author: Marina V. Evans, Ph.D., US EPA, MD B143-01, Research Triangle Park, NC 27711, Email: evans.marina{at}epa.gov, Phone: (919) 541- 0838, Fax: (919) 541- 3680

Received February 12, 2008; revision received April 9, 2008; accepted April 11, 2008


  Abstract

A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMAV) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMAV intravenously. The final model structure was based on diffusion limitation kinetics. In general, PBPK models use the assumption of blood flow-limited transport into tissues. This assumption has historically worked for small lipophilic organic solvents. However, the conditions under which flow-limited kinetics occurs and how to distinguish when flow-limited versus diffusion-limited transport is more appropriate, have been rarely evaluated. One important goal of this modeling effort was to systematically evaluate descriptions of flow-limited compared to diffusion-limited tissue distribution for DMAV, using the relatively extensive pharmacokinetic data available in mice. The diffusion-limited model consistently provided an improved fit over flow-limited simulations when compared to tissue time course iv experimental data. After model calibration, an independent data set obtained by oral gavage of DMAV, was used to further test model structure. Sensitivity analysis of the two PBPK model structures showed the importance of early time course data collection, and the impact of diffusion for kidney time course data description. In summary, this modeling effort suggests the importance of availability of organ specific time course data sets necessary for the discernment of PBPK modeling structure, motivated by knowledge of biology, and providing necessary feedback between experimental design and biological modelers.

Key Words: Physiologically-based pharmacokinetic (PBPK) model; Toxicokinetics; dimethylarsinic acid.


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