A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide: relevance of extrahepatic metabolism

A physiologically-based pharmacokinetic (PB-PK) model was developed for eth ylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen cr nl., 1997). In the presen t study, this PB-FK model has been validated for the rat. In addition, new data were used for the human class Theta GST T1-1. Validation experiments a re described in order to test the predictive value of kinetics to describe "whole-body" metabolism. For the validation experiments, groups of cannulat ed rats were dosed orally or intravenously with different doses of EDB. Obt ained blood concentration-time curves of EDB for all dosing groups were com pared to model predictions. It appeared that metabolism, which previously w as 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. W ith this extended model, the blood concentrations were much more accurately described compared to the predictions of the "liver-model". Therefore, ext rahepatic metabolism was also included in the human model. The present stud y 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 unders tand and predict in,vivo data, (C) 2000 Elsevier Science Ltd. All rights re served.