In Vitro-based and In Vivo-hased Simulations of Benzene Uptake and Metabolism in Rats

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Abstract
The metabolism of benzene was modelled in the rat by application of a physiologically based pharmacokinetic (PBPK) model. The model parameters were set by using reference physiological parameter values and reported partition coefficients from in vitro studies. Three sets of Vmax and Km values for benzene, derived from published in vitro studies, were substituted into the model while keeping all other model parameters constant. These model simulations were compared with two sets of empirical data on the metabolism or uptake of benzene after inhalation exposure. It was observed that the biotransformation parameter sets derived in vitro predicted all empirical data within a factor of two. In addition, it was observed that simulations across the two sets of empirical data which used biotransformation parameters obtained by fitting to one set of data to simulate the other set, led to results comparable to those in the in vitro-based simulations. It is concluded that the results of in vitro studies can be directly applied in a PBPK model in order to estimate the in vivo uptake and metabolism of benzene on the basis of previously determined model parameter assumptions. These results support earlier studies on the application of in vitro techniques for deriving PBPK model parameters. On the basis of other studies on the simulation of benzene kinetics, it is also concluded that additional studies are required to extend the validity of this approach for other compounds.