DIFFERENCES IN INTRINSIC EFFICACY OF BENZODIAZEPINES ARE REFLECTED IN THEIR CONCENTRATION-EEG EFFECT RELATIONSHIP

1 The relevance of EEG effect parameters as a measure of the central nervous system effects of benzodiazepines was evaluated. The concentration-EEG effect relationships of the benzodiazepine agonist midazolam, partial agonist bretazenil, antagonist flumazenil and inverse agonist Ro 19-4603 were quantified and compared with the intrinsic efficacy and affinity of these compounds at the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. 2 The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous bolus administration of 5 mg kg-1 midazolam, 2.5 mg kg-1 bretazenil, 10 mg kg-1 flumazenil or 2.5 mg kg-1 Ro 19-4603 to male Wistar derived rats. In a separate experiment the distribution between blood, cerebrospinal fluid and brain concentrations of these compounds was determined. A sensitive assay was developed to measure bretazenil and Ro 19-4603 concentrations in small samples of biological fluids. 3 The benzodiazepine-induced changes in amplitudes in the 11.5-30 Hz frequency band, as determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modelling procedure and in the case of midazolam, bretazenil and Ro 19-4603 successfully quantified by the sigmoidal E(max) model. Large differences in maximal effect of midazolam (E(max) = 73 +/- 2-mu-Vs-1), bretazenil (E(max) = 19 +/- 1-mu-Vs-1) and Ro 19-4603 (E(max) = -6.5 +/- 0.4-mu-Vs-1) were observed, reflecting their differences in intrinsic efficacy. A close correlation was found between the EC50 values based on free drug concentration and receptor affinity as determined by displacement of [H-3]-flumazenil in a washed brain homogenate at 37-degrees-C. In the concentration range of receptor saturation flumazenil did not produce any changes in the EEG effect measure. 4 The study demonstrated that the change in amplitudes in the 11.5-30 Hz frequency band of the EEG is a relevant measure of the pharmacological effect intensity of benzodiazepines, because it seems to reflect their affinity and intrinsic efficacy at the central GABA-benzodiazepine receptor complex.