Oe. Dellapaschoa et al., PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ANTICONVULSANT AND ELECTROENCEPHALOGRAM EFFECTS OF PHENYTOIN IN RATS, The Journal of pharmacology and experimental therapeutics, 284(2), 1998, pp. 460-466
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.