You are here:
THE INFLUENCE OF SERUM BINDING PROTEINS AND FEEDBACK CONTROL OF SERUM ESTRADIOL LEVELS ON THE COMPARATIVE POTENCY OF ENDOCRINE ACTIVE COMPOUNDS
Citation:
Teeguarden, J. AND H A. Barton. THE INFLUENCE OF SERUM BINDING PROTEINS AND FEEDBACK CONTROL OF SERUM ESTRADIOL LEVELS ON THE COMPARATIVE POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. Presented at SOT, San Francisco, CA, March 25-29, 2001.
Description:
THE INFLUENCE OF SERUM BINDING PROTEINS ON THE COMPARATIVE RECEPTOR BINDING POTENCY OF ENDOCRINE ACTIVE COMPOUNDS. JG Teeguarden1 and HA Barton2. 1ICF Consulting, Research Triangle Park NC; 2US EPA, ORD, NHEERL, ETD, Pharmacokinetics Branch, RTP, NC.
Accurate comparison of the receptor-binding potency (RBP) of endocrine active compounds (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 RBP 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. The in vitro model reproduced experimental measures of genistein and estradiol (E2) free fraction in human male serum, and was used to predict free fractions of each compound in human female and human pregnancy serum as well as adult and neonatal rat serum. Rat serum increased the relative RBP of genistein 6 fold relative to in vitro experiments conducted in the absence of serum proteins. Furthermore, simulations of E2 and genistein administration to adult rats demonstrated the additional influence of differential pharmacokinetics on the relative RBP of these compounds in vivo. In vivo, the relative RBP of genistein was less than that predicted in vitro (4.5 vs. 6.3), reflecting differential clearance of E2 and Genistein. These analyses demonstrate that predicting biological activity of EACs requires accounting for a variety of pharmacokinetic and pharmacodynamic considerations not typically captured in in vitro binding experiments used for screening RBP. The approaches developed in these models can be integrated into pharmacokinetic models to create more accurate descriptions of the distribution, clearance and receptor binding activity of EACs. Such biologically based models provide insight into the dose-response behaviors of EAC's and encourage development of improved methods for evaluating the biological activity of EACs. (This abstract does not represent EPA policy)