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

Purpose. A mechanism-based model is applied to analyse adaptive changes in the pharmacodynamics of benzodiazepines upon chronic treatment in rats. Methods. The: pharmacodynamics of midazolam was studied in rats which recei ved a constant rate infusion of the drug for 14 days, resulting in a steady -state concentration of 102 +/- 8 ng . ml(-1). Vehicle treated rats were us ed as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The Results were compared to data obtained i n vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEG effect wa s non-linear. In midazolam pre-treated rats the maximum EEG effect was redu ced by 51 +/- 23 mu V from the original value of 109 +/- 15 mu V in vehicle treated group. Analysis of this change on basis of the operational model o f agonism showed that it can be explained by a change in the parameter tiss ue maximum (E-m) rather than efficacy (tau). In the in vitro studies no cha nges in density, affinity or functionality of the benzodiazepine receptor w ere observed. Conclusions. 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.