Amitriptyline (AT) and its demethyl metabolite nortriptyline (NT) were given orally and i.m. to 6 normal subjects, and the areas under the blood concentration-time curves (AUC) were calculated. The mean unbound fraction of AT and NT in plasma was 5.4% and 8.3%, respectivley. The blood-plasma ratio of NT was nearly double that of AT, which was close to unity. The mean systemic availability of oral relative to i.m. AT and NT was 43% and 61%. The calculated mean oral blood clearance of AT as measured by dose (oral)/AUC was 1.61/min. The demethylation of orally administered AT varied considerably between the 6 individuals (from 25-89%) and correlated with oral drug clearance. Demethylation was estimated from the AUC applied to the NT metabolite. The estimated oral clearance of AT from demethylation ranged from 0.21-1.80 l/min.