ToxSci Advance Access published online on February 15, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj133
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, 80523-1680
* To whom correspondence should be addressed. Physiologically based pharmacokinetic (PBPK) modeling is generally for describing xenobiotic disposition in animals and humans with normal physiological conditions. We describe here an updated PBPK model for hexachlorobenzene (HCB) in male F344 rats with the incorporation of pathophysiological conditions. Two more features contribute to the distinctness of this model from the earlier published versions. This model took erythrocyte binding into account, and a particular elimination process of HCB, the plasma-to-gastrointestinal (GI) lumen passive diffusion (i.e., exsorption), was incorporated. Our PBPK model was developed using data mined from multiple pharmacokinetic studies in the literature, and then modified to simulate HCB disposition under the conditions of our integrated pharmacokinetics/liver foci bioassay. This model included plasma, erythrocytes, liver, fat, and rapidly and slowly perfused compartments and GI lumen. To account for the distinct characteristics of HCB absorption, the GI lumen was split into an upper and a lower part. HCB was eliminated through liver metabolism and the exsorption process. The pathophysiological changes after partial hepatectomy, such as alterations in the liver and body weights and fat volume, were incorporated in our model. With adjustment of the transluminal diffusion-related parameters, the model adequately described the data from the literature and our bioassay. Our PBPK model simulation suggests that HCB absorption and exsorption processes depend on exposure conditions; different exposure conditions dictate different absorption and exsorption rates. This model forms a foundation for our further exploration of the quantitative relationship between HCB exposure and development of preneoplastic liver foci.
Received October 9, 2005
Accepted January 27, 2006
Biotransformation and Toxicokinetics
An Updated PBPK Model for Hexachlorobenzene: Incorporation of Pathophysiological States Following Partial Hepatectomy and Hexachlorobenzene Treatment
Yasong Lu 1,
Manupat Lohitnavy 1,
Micaela B. Reddy 2,
Ornrat Lohitnavy 1,
Amanda Ashley 3,
and
Raymond S.H. Yang 1 *
2 DMPK Group, Preclinical Sciences, Roche Palo Alto LLC, CA, 94304
3 Department of Cell and Molecular Biology, Colorado State University, Fort Collins, CO, 80523
Raymond S.H. Yang, E-mail: raymond.yang{at}colostate.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Lohitnavy, Y. Lu, O. Lohitnavy, L. S. Chubb, S. Hirono, and R. S. H. Yang A Possible Role of Multidrug Resistance-Associated Protein 2 (Mrp2) in Hepatic Excretion of PCB126, an Environmental Contaminant: PBPK/PD Modeling Toxicol. Sci., July 1, 2008; 104(1): 27 - 39. [Abstract] [Full Text] [PDF]
|
|