Simulation of toluene kinetics in the rat by a physiologically based pharmacokinetic model with application of biotransformation parameters derived independently in vitro and in vivo.
The biokinetic behavior of toluene was modeled in the rat with a physiologically based pharmacokinetic (PB-PK) model. The model was parameterized by using reference physiological parameter values and partition coefficients that were reported earlier from in vitro studies. Biotransformation parameters for toluene, reported from two in vivo and six in vitro studies, were subsequently substituted in the model while keeping all other model parameters constant. Simulations of toluene kinetics, based on these eight biotransformation parameter sets, were compared with empirical data reported on toluene uptake in blood and/or brain tissue after inhalation exposure. It was observed that most empirical data on toluene blood concentrations were adequately predicted by the model for almost each of the eight biotransformation parameter sets. It was also observed that differences between model predictions, based on either in vivo- or in vitro-derived biotransformation parameters, were generally small. It is concluded that the results from most in vitro studies on toluene biotransformation can be applied successfully to predict the kinetics of toluene in vivo. It is also concluded that the brain-blood partition coefficient may be at least as important for the outcome of the model as the biotransformation parameters are. These results support earlier reported findings in the literature on application of in vitro techniques to derive parameters for PB-PK models.
DeJongh
J
J
Research Institute of Toxicology (RITOX), Utrecht, The Netherlands.
Blaauboer
B J
BJ
D000818:Animals; D001711:Biotransformation; D005260:Female; D016013:Likelihood Functions; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D014018:Tissue Distribution; D014050:Toluene / Q000493:pharmacokinetics*
D014050:Toluene