Use of a Physiologically Based Pharmacokinetic Model for Rats to Study the Influence of Body Fat Mass and Induction of CYP1A2 on the Pharmacokinetics of TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t(1/2)) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t(1/2) increases with dose, due to hepatic sequestration. Because experimental data indicate that the t(1/2) of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t(1/2) after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t(1/2). However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t(1/2) reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.