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A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat
- Source :
- Toxicology and Applied Pharmacology 231 (2008) 2, Toxicology and Applied Pharmacology, 231(2), 248-259
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
Abstract
- The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene estragole in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model consists of eight compartments including liver, lung and kidney as metabolizing compartments, and additional compartments for fat, arterial blood, venous blood, rapidly perfused tissue and slowly perfused tissue. Evaluation of the model was performed by comparing the PBBK predicted dose-dependent formation of the estragole metabolites 4-allylphenol and 1′-hydroxyestragole glucuronide to literature reported levels of these metabolites, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of estragole at different oral doses was examined. At low doses formation of 4-allylphenol, leading to detoxification, is observed to be the major metabolic pathway, occurring mainly in the lung and kidney due to formation of this metabolite with high affinity in these organs. Saturation of this metabolic pathway in the lung and kidney leads to a relative increase in formation of the proximate carcinogenic metabolite 1′-hydroxyestragole, occurring mainly in the liver. This relative increase in formation of 1′-hydroxyestragole leads to a relative increase in formation of 1′-hydroxyestragole glucuronide and 1′-sulfooxyestragole the latter being the ultimate carcinogenic metabolite of estragole. These results indicate that the relative importance of different metabolic pathways of estragole may vary in a dose-dependent way, leading to a relative increase in bioactiviation of estragole at higher doses. © 2008 Elsevier Inc. All rights reserved.
- Subjects :
- Male
Physiologically based pharmacokinetic modelling
mice
Metabolite
Allyl compound
Allylbenzene Derivatives
Anisoles
in-vitro
organic-chemicals
Pharmacology
Kidney
1'-hydroxyestragole
Toxicology
Models, Biological
species-differences
Rats, Sprague-Dawley
Biological pathway
chemistry.chemical_compound
Glucuronides
Phenols
naturally-occurring alkenylbenzenes
Animals
Tissue Distribution
Sulfones
Rats, Wistar
Lung
Toxicologie
Carcinogen
VLAG
Dose-Response Relationship, Drug
Chemistry
allylbenzene analogs
mouse-liver
Rats
Allyl Compounds
Metabolic pathway
Biochemistry
Inactivation, Metabolic
Carcinogens
Female
Estragole
Glucuronide
metabolism
post-labeling analysis
Subjects
Details
- ISSN :
- 0041008X
- Volume :
- 231
- Database :
- OpenAIRE
- Journal :
- Toxicology and Applied Pharmacology
- Accession number :
- edsair.doi.dedup.....578a11596c5a06688da0e89dd5c0a559