Mechanism-based modeling of adaptive changes in the pharmacodynamics of midazolam in the kindling model of epilepsy.
OBJECTIVE
A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo.


METHODS
The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEG effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (tau) and tissue maximum (Em) either separately or in combination. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation.


RESULTS
The relationship between midazolam concentration and EEG effect was non-linear. In kindled rats the maximum EEG effect was reduced by 27+/-8.3 microV from the original value of 94+/-4.4 microV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (tau). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent 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.
Cleton
A
A
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Van der Graaf
P H
PH
Ghijsen
W
W
Voskuyl
R
R
Danhof
M
M
D000222:Adaptation, Physiological; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D002713:Chlorine / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000503:physiopathology*; D018755:GABA Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007696:Kindling, Neurologic; D008297:Male; D008874:Midazolam / Q000097:blood / Q000494:pharmacology*; D009118:Muscimol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D018755:GABA Agonists; D009118:Muscimol; D002713:Chlorine; D008874:Midazolam