Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.

Article date: 2000/5/9

PubMed ID: 1850477

Journal name: Pharmaceutical research (ISSN: 0724-8741)


It is concluded that the observed changes in the concentration-EEG effect relationship of midazolam upon chronic treatment are unrelated to changes in benzodiazepine receptor function.


The pharmacodynamics of midazolam was studied in rats which received a constant rate infusion of the drug for 14 days, resulting in a steady-state concentration of 102 +/- 8 ng x ml(-1). Vehicle treated rats were used as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation.


The relationship between midazolam concentration and EEG effect was non-linear. In midazolam pre-treated rats the maximum EEG effect was reduced by 51 +/- 23 microV from the original value of 109 +/-15 microV in vehicle treated group. Analysis of this change on basis of the operational model of agonism showed that it can be explained by a change in the parameter tissue maximum (Em) rather than efficacy (tau). In the in vitro studies no changes in density, affinity or functionality of the benzodiazepine receptor were observed.

Author List: Cleton A, Odman J, Van der Graaf P H, Ghijsen W, Voskuyl R, Danhof M

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: GABA Agonists; GABA Modulators; Receptors, GABA-A; Tritium; Muscimol; Chlorine; Flunitrazepam; Midazolam;

Mesh terms: Adaptation, Physiological/drug effects; Animals; Biological Transport/drug effects; Brain Chemistry/drug effects; Chlorine/pharmacokinetics; Dose-Response Relationship, Drug; Electroencephalography/drug effects; Flunitrazepam/metabolism; GABA Agonists/pharmacology; GABA Modulators/pharmacokinetics; Male; Midazolam/pharmacokinetics; Models, Biological; Muscimol/pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, GABA-A/physiology; Tritium;

Citations: - gamma-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl- uptake in rat brain synaptoneurosomes: evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel.

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