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THE INFLUENCE OF SERUM BINDING PROTEINS AND CLEARANCE ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS
Citation:
Barton, H A. AND J. Teeguarden. THE INFLUENCE OF SERUM BINDING PROTEINS AND CLEARANCE ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. Presented at Annual American Chemistry Council's Long Range Research Initiative Science Meeting, Herndon, VA, June 24-25, 2003.
Description:
THE INFLUENCE OF SERUM BINDING PROTEINS AND CLEARANCE ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. JG Teeguarden1 and HA Barton2. 1ENVIRON International, Ruston LA; 2US EPA, ORD, NHEERL, ETD, Pharmacokinetics Branch, RTP, NC.
One measure of the potency of compounds which lead to adverse effects through ligand dependent gene transcription is the relative affinity for the critical receptor. Endocrine active compounds (EAC) that are presumed to act principally through binding to the estrogen receptor (ER), for example the isoflavone genistein, bisphenol A and octylphenol, is one such class of compounds. For purposes of making simple comparisons of potency, receptor binding affinity has been equated to potency, which consequently defines the dose-response characteristics for the compound. Direct extrapolation of these in vitro estimated potencies to the corresponding in vivo system and to specific species or life-stages (neonatal, pregnant) can be misleading. Accurate comparison of the receptor-binding potency (RBP) of EACs requires characterization of biochemical and pharmacokinetic factors that affect the bioavailable concentration. Quantitative in vitro and in vivo models have been developed for integrating factors (serum protein and receptor binding affinity, pharmacokinetics) that affect the relative binding potency of EACs. The approaches developed here provide a useful framework for utilizing experimental data from in vitro and in vivo studies to estimate the relative RBP of these compounds. Examples are presented to illustrate the utility of this model structure for integrating available information to conduct dose-response assessments of ER ligands (This abstract does not represent EPA policy).
Key Words: Endocrine Active Compounds
Dose Response
Estrogen Receptor Ligands
Physiologically Based Pharmacokinetic Model
Subject Category: Dose Response