Mechanism-based modeling of adaptive changes in the pharmacodynamics of midazolam in the kindling model of epilepsy

Purpose. A mechanism-based model is proposed for the analysis of adaptive c hanges in the pharmacodynamics of benzodiazepines in vivo. Methods. The pharmacodynamics of midazolam was studied in the kindling mode l of experimental epilepsy. Concentration-EEG effect data from kindled rats and their controls were fitted to the operational model of agonism. A step wise procedure was used, allowing changes in the parameters efficacy (tau) and tissue maximum (E-m) either separately or in combination. The results w ere compared to data obtained in vitro in a brain synaptoneurosomal prepara tion. Results. The relationship between midazolam concentration and EEG effect wa s non-linear. In kindled rats the maximum EEG effect was reduced by 27 +/- 8.3 mu V from the original value of 94 +/- 4.4 mu V. Analysis on the basis of the operational model of agonism showed that this decrease could be expl ained by a difference in the parameter system maximum (E-m) rather than eff icacy (tau). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, con sistent with the lack of a change in efficacy (tau). Conclusions. The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.