SEPARATION OF THE PHARMACOKINETIC PHARMACODYNAMIC PROPERTIES OF ORAL AND IV ADINAZOLAM MESYLATE AND N-DESMETHYLADINAZOLAM MESYLATE IN HEALTHY-VOLUNTEERS

Adinazolam, a triazolobenzodiazepine, has been studied in the treatment of depression, panic disorder and anxiety. N-Desmethyladinazolam (NDMAD), the primary metabolite of adinazolam. produces benzodiazepine-like psychomotor effects after adinazolam administration. The contribution of other adinazolam metabolites has not been assessed. NDMAD mesylate in 30mg doses was administered orally and as 30-minute IV infusions; corresponding oral and IV adinazolam mesylate doses were 30 and 15mg, respectively. All treatments were administered in a double-blind fashion to 16 male subjects in a 4-way crossover design. Plasma adinazolam and NDMAD concentrations were determined by high performance liquid chromatography (HPLC). Psychomotor performance was assessed by digit-symbol substitution (DSST) and card sorting tasks. Adinazolam and NDMAD pharmacokinetics were consistent with previous results. The absolute oral bioavailability of NDMAD was approximately 74%. The magnitude of psychomotor performance decrements followed this order: IV NDMAD > oral adinazolam = oral NDMAD > IV adinazolam, where > denotes a statistically significant difference. Fitting a sigmoidal E(max) model to pooled data for all treatments resulted in an EC50 of 324-mu-g/L for NDMAD. Psychomotor performance decrements after each treatment correlated well with plasma NDMAD concentrations. The results confirm that adinazolam has no effect on psychomotor performance at therapeutically relevant concentrations and demonstrate that NDMAD is the primary compound responsible for benzodiazepine-like psychomotor effects following adinazolam administration in humans.