Phannacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats

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Abstract
1 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. 2 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. 3 The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4 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 (Cmin) 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. 5 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 relatively narrow range of 0.01–0.30 mgl−1. 6 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 a rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.