Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.
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 microA 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 0.01-0.30mgI. 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.
Dingemanse
J
J
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Voskuyl
R A
RA
Langemeijer
M W
MW
Postel-Westra
I
I
Breimer
D D
DD
Meinardi
H
H
Danhof
M
M
D000818:Animals; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D005260:Female; D008954:Models, Biological; D010076:Oxazepam / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000927:Anticonvulsants; D010076:Oxazepam