Pharmacokinetics of ( sup 125 I)-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: Analysis with a physiological modeling approach
- Syntex Corporation, Palo Alto, CA (USA)
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. (125I)-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction.
- OSTI ID:
- 6747844
- Journal Information:
- Toxicology and Applied Pharmacology; (USA), Journal Name: Toxicology and Applied Pharmacology; (USA) Vol. 103:3; ISSN TXAPA; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADIPOSE TISSUE
ANIMAL TISSUES
ANIMALS
BETA DECAY RADIOISOTOPES
BODY
CELL CONSTITUENTS
CONNECTIVE TISSUE
DAYS LIVING RADIOISOTOPES
DIGESTIVE SYSTEM
DIOXIN
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
ELECTRON CAPTURE RADIOISOTOPES
GLANDS
HETEROCYCLIC COMPOUNDS
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LIGANDS
LIVER
MAMMALS
MATHEMATICAL MODELS
METABOLISM
METABOLITES
MICE
MICROSOMES
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
RADIOISOTOPES
RIBOSOMES
RODENTS
TISSUE DISTRIBUTION
TISSUES
TRACER TECHNIQUES
VERTEBRATES