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USE OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL (PBPK) FOR RATS TO STUDY THE INFLUENCE OF BODY FAT MASS AND INDUCTION OF CYP1A2 ON THE PHARMACOKINETICS OF TCDD
Citation:
EMOND, C., L. S. BIRNBAUM, AND M. J. DEVITO. USE OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL (PBPK) FOR RATS TO STUDY THE INFLUENCE OF BODY FAT MASS AND INDUCTION OF CYP1A2 ON THE PHARMACOKINETICS OF TCDD. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 114(9):1394-400, (2006).
Impact/Purpose:
To better understand the role of lipid partitioning, hepatic sequestration and hepatic metabolism in the pharmacokinetics of TCDD
Description:
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical which distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces CYP1A2 that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination of TCDD. This model was then used to understand the role of lipid partitioning, hepatic sequestration and hepatic metabolism in the pharmacokinetics of TCDD. Objectives of this work were 1)- to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t½) of TCDD using a PBPK model; and 2)- to evaluate the terminal elimination t½ in presence or absence of CYP1A2 binding. When the model assumes a fixed elimination of TCDD, t½ increases with dose, due to hepatic sequestration. Because experimental data indicate that the t½ of TCDD decreases with dose, the model was modified to include inducible elimination. The PBPK model was then used to compare the t½ following an increase of adipose tissue mass fraction from 6.9 to 70%. The model estimates that at low exposures, increasing adipose tissue mass increases the terminal t½. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t½ reaches a plateau. This demonstrates that inducible elimination is needed in a PBPK model in order to describe the pharmacokinetics of TCDD and that at low exposures, these models are more sensitive to parameters related to partitioning into adipose tissue.