| Abstrakt: |
The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic–pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5–30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emaxpharmacodynamic model. Significant differences in both EC50and Emaxwere observed. The values of the EC50were 76±11, 12±3, and 512±116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emaxwere 113±9, 44±3, and 175±10 μV/s. In the presence of ethanol the values of the EC50of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emaxand Hill-factor were unchanged. Due to a large interindividual variability no significant change in EC50was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPDfor all three drugs, indicating that changes in EC50can be explained entirely by a change in the apparent affinity constant KPDwithout concomitant changes in the efficacy parameter ePDand the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine. |
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