PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ANTICONVULSANT AND ELECTROENCEPHALOGRAM EFFECTS OF PHENYTOIN IN RATS

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrat ed approach to characterize the pharmacokinetic-pharmacodynamic relati onship of phenytoin. In parallel, the anticonvulsant effect and the el ectroencephalogram (EEG) effect were used td determine the pharmacodyn amics Male Wistar-derived rats received a single intravenous dose of 4 0 mg.kg(-1) phenytoin. The increase in the threshold for generalized s eizure activity (TGS) was used as the anticonvulsant effect and the in crease in the total number of waves in the 11.5 to 30 Hz frequency ban d was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis Menten elimina tion V-max and K-m values were, respectively, 386 +/- 31 mu g.min(-1) and 15.4 +/- 2.2 mu g.ml(-1) for the anticonvulsant effect in the cort ical stimulation model and 272 +/- 31 mu g.min(-1) and 5.9 +/- 0.7 mu g.ml(-1) for the EEG effect. In both groups, a delay to the onset of t he effect was observed relative to plasma concentrations. The relation ship between phenytoin plasma concentrations and effect site was estim ated by an equilibration kinetics routine, yielding mean k(e0) values of 0.108 and 0.077 min(-1) for the anticonvulsant and EEG effects, res pectively. The EEG changes in the total number of waves could be fitte d by the sigmoid E-max model, but E-max values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E = E-0 + B-n.C-n) derived from the s igmoid E-max model was applied to describe the concentration-anticonvu lsant effect relationship, under the assumption that E-max values cann ot be reached within acceptable electric stimulation levels. This appr oach yielded a coefficient (B) of 2.0 +/- 0.4 mu A.ml.mu g(-1) and an exponent (n) of 2.7 +/- 0.9. The derived EC50 value of 12.5 +/- 1.3 mu g.ml(-1) for the EEG effect coincides with the ''therapeutic range'' in humans.