Title
A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide: Relevance of extrahepatic metabolism
Author
Hissink, A.M.
Wormhoudt, L.W.
Sherratt, P.J.
Hayes, J.D.
Commandeur, J.N.M.
Vermeulen, N.P.E.
van Bladeren, P.J.
Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding
Publication year
2000
Abstract
A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new data were used for the human class ΘGST T1-1. Validation experiments are described in order to test the predictive value of kinetics to describe 'whole-body' metabolism. For the validation experiments, groups of cannulated rats were dosed orally or intravenously with different doses of EDB. Obtained blood concentration-time curves of EDB for all dosing groups were compared to model predictions. It appeared that metabolism, which previously was assumed to be restricted to the liver, was underestimated. Therefore, we extended the PB-PK model to include all the extrahepatic organs, in which the enzymes involved in EDB metabolism have been detected and quantified. With this extended model, the blood concentrations were much more accurately described compared to the predictions of the 'liver-model'. Therefore, extrahepatic metabolism was also included in the human model. The present study illustrates the potential application of in vitro metabolic parameters in risk assessment, as well as the use of PB-PK modelling as a tool to understand and predict in vivo data.
Subject
Ethylene dibromide
Extrapolation
Glutathione S-transferase
Interindividual variation
PBPK
Risk assessment
1,2 dibromoethane
Cytochrome P450
Glutathione transferase
Animal experiment
Biotransformation
Controlled study
Pharmacokinetics
Prediction
Toxicity testing
Xenobiotic metabolism
Administration, Oral
Area Under Curve
Chromatography, Gas
Cytochrome P-450 Enzyme System
Glutathione Transferase
Injections, Intravenous
Models, Biological
To reference this document use:
http://resolver.tudelft.nl/uuid:41010b49-00ed-4135-ba00-5c81b22f33fe
DOI
https://doi.org/10.1016/s0278-6915(00)00059-4
TNO identifier
41572
Publisher
Elsevier, Amsterdam
Source
Food and Chemical Toxicology, 38, 707-716
Document type
article