title: Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.
abstract: OBJECTIVE
  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 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Division of Pharmacology, Leiden Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Cleton
authors.forename: J
authors.initials: J
authors.lastname: Odman
authors.forename: P H
authors.initials: PH
authors.lastname: Van der Graaf
authors.forename: W
authors.initials: W
authors.lastname: Ghijsen
authors.forename: R
authors.initials: R
authors.lastname: Voskuyl
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002713:Chlorine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008954:Models, Biological; D009118:Muscimol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D014316:Tritium
chemical_list: D018755:GABA Agonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D014316:Tritium; D009118:Muscimol; D002713:Chlorine; D005445:Flunitrazepam; D008874:Midazolam