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2007 CompTox Forum
Abstract - Driving Towards the Boundary between Tissue Dosimetry and Dynamics through Integration of Receptor Binding and Pharmacokinetics in a PBPK Model for Estradiol
Justin Teeguarden and David Plowchalk
Justin Teeguarden, Ph.D., DABT (presenting author)
Senior Research Scientist
Pacific Northwest National Laboratory
902 Battelle Boulevard, P.O. Box 999, MSIN P7 59, Richland, WA 99352
Phone: 509-376-4262
E-mail: justin.teeguarden@pnl.gov
Endocrine active compounds (EACs) are a structurally diverse group of chemicals that impact the endocrine system, in some cases involving dysregulation of the Hypothalamic-Pituitary-Gonadal axis. Estradiol (E2) is a prototypical estrogenic EAC that regulates numerous endocrine functions through binding to the estrogen receptor. To better appreciate the dose-dependencies of physiologic responses produced by E2 in target tissues, a physiologically-based pharmacokinetic (PBPK) model for E2 in rats and humans (male and female) was developed. The model integrates pharmacokinetics and protein/receptor binding to describe the uptake, distribution, and clearance of E2 following oral and intravenous administration. The model was used to evaluate the impact of plasma protein binding on E2 liver uptake and uterine receptor binding. The E2 PBPK model may be considered a framework for integrating the processes that influence EAC pharmacokinetics and tissue response—receptor binding affinity, receptor distribution, restriction of free EAC concentrations via plasma binding proteins, tissue kinetics, and clearance—for evaluating the biological activity of EACs. An overview of the development of the model with an emphasis on key processes controlling target tissue receptor binding will be presented.