PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ANTICONVULSANT EFFECT OF OXAZEPAM IN INDIVIDUAL RATS

The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean ± s.e., n = 11) of clearance and volume of distribution were 28 ± 2 ml min-1 kg-1 and 2.6 ± 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within on rat. Significant dose-dependent elevations of the seizure threshold were observed. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean ± s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (C(min)) were 243 ± 27 μA and 0.11 ± 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 ± 18%. The value of the minimal effective concentration was in each animal and on each occasion close to zero within the relative narrow range of 0.01-0.30 mg l-1. The results of this study showed that it is possible to determine in vivo concentration-anticonvulsant effect relationships of oxazepam under non-steady-state conditions in individual rats. The anti-convulsant effect of oxazepam appeared to be rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.