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

Environ Health Perspect. 2006 Sep;114(9):1394-400. doi: 10.1289/ehp.8805.

Abstract

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 (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 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 t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects*
  • Adipose Tissue / metabolism
  • Animals
  • Body Weight / drug effects*
  • Body Weight / physiology
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / toxicity*
  • Enzyme Induction / drug effects*
  • Enzyme Induction / physiology
  • Female
  • Half-Life
  • Male
  • Polychlorinated Dibenzodioxins / administration & dosage
  • Polychlorinated Dibenzodioxins / pharmacokinetics*
  • Polychlorinated Dibenzodioxins / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution

Substances

  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins
  • Cytochrome P-450 CYP1A2