The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ₁ receptor 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 E_max pharmacodynamic model. Significant differences in both EC₅₀ and E_max were observed. The values of the EC₅₀ were 76±11, 12±3, and 512±116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the E_max were 113±9, 44±3, and 175±10 V/s. In the presence of ethanol the values of the EC₅₀ of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for E_max and Hill-factor were unchanged. Due to a large interindividual variability no significant change in EC₅₀ was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant K_PD for all three drugs, indicating that changes in EC₅₀ can be explained entirely by a change in the apparent affinity constant K_PD without concomitant changes in the efficacy parameter e_PD and 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 BZ₁ receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine.