PLASMA AND BRAIN PHARMACOKINETICS OF AMITRIPTYLINE AND ITS DEMETHYLATED AND HYDROXYLATED METABOLITES AFTER ACUTE INTRAPERITONEAL INJECTION IN MICE

The fate of amitriptyline (AMI) and its demethylated and hydroxylated metabolites was studied in Swiss CD1 mice, after acute intraperitoneal injection of AMI (20 mg/kg). Levels of each compound were determined to establish pharmacokinetic parameters in plasma and brain. Absorptio n and elimination of AMI were rapid (t(max) = 0.37 h and 0.42 h, and t (1/2) = 3.2 h and 3.6 h in plasma and brain, respectively). In plasma, 10-OH-nortriptyline was the main metabolite (46% of AUC) and 10-OH-am itriptyline reached significant levels but only during the first hour. In brain, AMI (43% of total AUC), nortriptyline (NOR) (29%) and demet hylnortriptyline (DM-NOR) (11%) were the most abundant compounds, poss ibly through high brood-brain barrier transfer and/or marked intracere bral demethylation. Brain OH-metabolite levels were much lower. Knowle dge of kinetic parameters and metabolism of AMI can help in the evalua tion of pharmacological activity.