A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.
A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.
Leung
H W
HW
Syntex Corporation, Palo Alto, California 94304.
Paustenbach
D J
DJ
Murray
F J
FJ
Andersen
M E
ME
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism; D003600:Cytosol / Q000648:ultrastructure; D004147:Dioxins / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D001189:Aryl Hydrocarbon Hydroxylases