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 (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.
Emond
Claude
C
National Research Council, National Academy of Sciences, Washington, DC, USA.
Birnbaum
Linda S
LS
DeVito
Michael J
MJ
D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006207:Half-Life; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D019388:Cytochrome P-450 CYP1A2