title: Mechanism-based pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo correlations.
abstract: A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta-carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC50) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (KPD) and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 +/- 0 ng.ml(-1) for bretazenil to 436 +/- 72 ng.ml(-1) for clobazam and the values for e(PD) from -0.27 +/- 0 for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate to 0.54 +/- 0.02 for diazepam. Significant linear correlations were observed between KPD for unbound concentrations and the affinity in an in vitro receptor bioassay (r = 0.93) and between e(PD) and the GABA-shift in vitro (r = 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists relative to neuroactive steroids.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: S A G
authors.initials: SA
authors.lastname: Visser
authors.forename: F L C
authors.initials: FL
authors.lastname: Wolters
authors.forename: J M
authors.initials: JM
authors.lastname: Gubbens-Stibbe
authors.forename: E
authors.initials: E
authors.lastname: Tukker
authors.forename: P H
authors.initials: PH
authors.lastname: Van Der Graaf
authors.forename: L A
authors.initials: LA
authors.lastname: Peletier
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000465:Algorithms; D000818:Animals; D053961:Azabicyclo Compounds; D001569:Benzodiazepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003292:Convulsants / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects*; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013056:Spectrophotometry, Ultraviolet; D000077334:Zolpidem
chemical_list: D053961:Azabicyclo Compounds; D002243:Carbolines; D003292:Convulsants; D018755:GABA Agonists; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; C515050:zopiclone; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D000077334:Zolpidem