Kinetics and neuropsychologic effects of IV diazepam in the presence and absence of its active N-desmethyl metabolite in humans.

In 12 healthy volunteers the kinetics and neuropsychological actions of IV diazepam (DZ) (single dose) were studied with and without the presence of its main metabolite N-desmethyldiazepam (NDDZ). Both the maximal plasma concentration and the steepness of the alpha-slope were correlated with variations in the corresponding continuous reaction time (CRT). EEG profiles, CRT and clinical ratings for anxiety and sedation all showed significant changes between the situations with the metabolite present or absent, but no significant correlation could be found with the kinetic pattern of DZ in the two situations. Tolerance to NDDZ did not develop. The results indicate that the presence of the active metabolite changes the pharmacodynamic profile of the parent compound probably by an interaction at the receptor site between DZ and NDDZ. Changes in the spectrum of effects during long-term therapy with DZ may, therefore, partly be explained in this way.