A physiologically-based pharmacokinetic(PB-PK) model for ethylene dibromide: relevance of extrahepatic metabolism.
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 ThetaGST 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.
Hissink
A M
AM
TNO Nutrition and Food Research Institute, Toxicology Division, PO Box 360, 3700 AJ Zeist, The Netherlands. hissink@voeding.tno.nl
Wormhoudt
L W
LW
Sherratt
P J
PJ
Hayes
J D
JD
Commandeur
J N
JN
Vermeulen
N P
NP
van Bladeren
P J
PJ
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015946:Ethylene Dibromide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment
D015946:Ethylene Dibromide; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase