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Phannacokinetic‐pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats
Author(s) -
Dingemanse Jasper,
Voskuyl Rob A.,
Langemeijer Mariska W.E.,
PostelWestra Ineke,
Breimer Douwe D.,
Meinardi Harry,
Danhof Meindert
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14653.x
Subject(s) - oxazepam , anticonvulsant , pharmacodynamics , pharmacokinetics , pharmacology , chemistry , in vivo , medicine , epilepsy , benzodiazepine , biology , receptor , biochemistry , psychiatry , microbiology and biotechnology
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 (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. 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.