The Influence of Obesity on the Pharmacokinetics of Dioxin in Mice: An Assessment Using Classical and PBPK Modeling

• Published in: Toxicological sciences Vol. 164; no. 1; pp. 218 - 228
• Main Authors: Emond, Claude, DeVito, Michael J, Diliberto, Janet J, Birnbaum, Linda S
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.07.2018
• Subjects: Animals; Computer Simulation; Cytochrome P-450 CYP1A2 - genetics; Diet, High-Fat - adverse effects; Gene Expression - drug effects; Half-Life; Inactivation, Metabolic; Liver - drug effects; Liver - metabolism; Lung - drug effects; Lung - metabolism; Male; Mice; Mice, Inbred C57BL; Models, Biological; Obesity - metabolism; Obesity and Dioxin Pbpk; Polychlorinated Dibenzodioxins - blood; Polychlorinated Dibenzodioxins - pharmacokinetics; Species Specificity; Tissue Distribution; PBPK; pharmacokinetics; TCDD; dioxin; obesity
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfy078

Abstract The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 μg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.