A Physiologically Based Pharmacokinetic Model for 2,3,7,8-Tetrabromodibenzo- p-dioxin (TBDD) in the Rat: Tissue Distribution and CYP1A Induction

Abstract

Biologically based models serve as valuable tools for integration of mechanistic pharmacokinetic data by their explicit definition of important determinants of chemical disposition. The objective of the present work was to develop a physiologically based pharmacokinetic model to describe the disposition and enzyme induction properties of 2,3,7,8-tetrabromodibenzo- p-dioxin (TBDD). The TBDD model, which was based on models previously developed for 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), incorporated: ternary interactions between TBDD, the Ah receptor, and specific DNA-binding sites; induction of a TBDD-binding protein specific to the liver; and diffusion-limited tissue uptake. In the model for TBDD, CYP1A2, which had been measured directly by radioimmunoassay, was assumed to be the hepatic binding protein. The model employed physiologic parameters based on recent data in unanesthetized rats, growing tissue compartments, transluminal excretion of parent TBDD via the gut into the feces, and a separate skin compartment. The model was developed using tissue distribution and excretion data following a single intravenous dose of 1 nmol [ 3H]TBDD per kilogram. The TBDD model was then used unchanged to analyze several experimental data sets illustrating the time, dose, and route of exposure dependency of TBDD disposition. The model successfully described the dose-dependent tissue distribution of [ 3H]TBDD following intravenous and oral administration and following a single dermal dose. These studies show that diffusional clearance from blood to tissue was slower for skin than for fat (PA sk ∼ 0.1 PA f). When compared with TCDD: (i) TBDD had a higher fat partition coefficient (P f = 1000 vs 400) and a lower diffusional clearance into fat (PA f = 0.1 vs 0.2) than TCDD; (ii) the binding affinity of CYP1A2 for TBDD was slightly lower than that for TCDD (9.0 vs 6.5 nM); and (iii) TBDD exhibited a slightly greater rate of metabolic elimination (2.0 vs 1.65). Small differences were noted in DNA binding parameters derived for the induction of CYPlAl and CYP1A2 for TBDD versus TCDD. With minor modifications, the biologically based model for TCDD accurately described the behavior of the brominated congener. The present model, which relied on measured values ofCYP1A2 and specified CYP1A2 as the hepatic dioxin binding species, successfully describes the hepatic disposition of TBDD, providing further evidence that CYP1A2 is the primary hepatic binding species in the rat.