Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABAA Receptor Modulators: In Vitro-in Vivo Correlations

• Published in: The Journal of pharmacology and experimental therapeutics 2003-01, Vol.304 (1), p.88-101
• Main Authors: Visser, S.A.G., Wolters, F.L.C., Gubbens-Stibbe, J.M., Tukker, E., van der Graaf, P.H., Peletier, L.A., Danhof, M.
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Azabicyclo Compounds; Benzodiazepines - pharmacology; Carbolines - pharmacology; Chromatography, High Pressure Liquid; Convulsants - pharmacology; Electroencephalography - drug effects; GABA Agonists - pharmacology; GABA Modulators - pharmacology; Hypnotics and Sedatives - pharmacology; In Vitro Techniques; Infusions, Intravenous; Male; Models, Biological; Piperazines - pharmacology; Protein Binding; Pyridines - pharmacology; Rats; Rats, Wistar; Receptors, GABA-A - drug effects; Spectrophotometry, Ultraviolet
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.042341

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 GABAAreceptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one β-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 ePD from −0.27 ± 0 for methyl 6,7-dimethoxy-4-ethyl-β-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 ePD 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.