You are here:
COMPUTATIONAL MODELING OF SERUM BINDING PROTEINSAND CLEARANCE IN EXTRAPOLATIONS ACROSS LIFE-STAGES AND SPECIES FOR ENDOCRINE ACTIVE COMPOUNDS
Citation:
Teeguarden, J. AND H A. Barton. COMPUTATIONAL MODELING OF SERUM BINDING PROTEINSAND CLEARANCE IN EXTRAPOLATIONS ACROSS LIFE-STAGES AND SPECIES FOR ENDOCRINE ACTIVE COMPOUNDS. RISK ANALYSIS. Blackwell Publishing, Malden, MA, 24(3):751, (2004).
Impact/Purpose:
Accurate comparison of the receptor-binding potency of endocrine active compounds requires characterization of biochemical and pharmacokinetic factors that affect the bioavailable concentration. The available data for parameterizing these models for several EAC's was evaluated
Description:
One measure of the potency of compounds that lead to adverse effects through ligand-dependent gene transcription is the relative affinity for the critical receptor. Endocrine active compounds that are presumed to act principally through binding to the estrogen receptor (e.g. genistein, bishphenol A, octylphenol) comprise 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 (e.g. neonatal, pregnancy) can be misleading. Accurate comparison of the receptor-binding potency of endocrine active compounds 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 (e.g. serum protein and receptor binding affinities, pharmacokinetics) that affect the relative receptor binding potency. The available data for parameterizing these models for several EAC's was evaluated and the models were validated and excersized within the limitations imposed by the quality of the available data to demonstrate the impact of serum binding and differential clearance on receptor binding potency. The examples illustrate the utility of this model structure for integrating available experimental data from in vitro and in vivo studies to estimate the relative binding potency of these compounds and to conduct dose-response assessment for ER ligands.