Prediction of the concentration of diphenylhydantoin in the brain using a physiological pharmacokinetic hybrid model

Abstract

A physiological pharmacokinetic hybrid model was developed in order to predict the disposition kinetics of diphenylhydantoin (DPH) in the brain from the plasma concentration data of DPH. The model was constructed under the assumptions of well-stirred, plasma flow-limited and linear tissue disposition kinetics of DPH. DPH was administered intravenously to the rats at a dose of 10 mg/kg together with/without sodium salicylate (SA; 10 mg/kg) and the DPH concentrations in the plasma and brain were determined. Plasma protein binding of DPH was also determined using equilibrium dialysis technique. Then the model was tested for its predictability of DPH concentrations in the brian from the plasma data of DPH. It was found that the predicted values of DPH concentrations in the brian were in fair agreement with the experimental values in the rats of both treaments. The 2-fold increase in the brain concentrations of DPH by SA-coadministration was predicted well from the plasma concentration and plasma free fraction (f p) data of DPH using the model. Therefore, the hybrid model was concluded to be very useful for the prediction of the concentrations of DPH in the brain from the plasma concentration data. Finally, DPH concentrations in the human brian was calculated using this model from plasma DPH data in the literature, yet the scale-up of this model to the human is not convinced.