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 doubleblind 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 Emax model to pooled data for all treatments resulted in an EC50 of 324 γg/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 thera-peutically relevant concentrations and demonstrate that NDMAD is the primary compound responsible for benzodiazepine-like psychomotor effects following adinazolam administration in humans.