Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 mg/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug.

The urinary excretion of amitriptyline (AMT) and seven of its metabolites was studied by mass spectrometry in 10 depressive in-patients treated to steady-state condition with oral amitriptyline. An average of 68.3% of the dose was recovered in the urine, of which 68.6% was present as conjugates. Hydroxynortriptyline and its conjugate represented 54% of the total recovery. There was marked variation in metabolite pattern between patients. The variations were not due to concomitant medication with benzodiazepines. There was no correlation between the plasma and urine concentrations of AMT and its metabolites, except for amitriptyline conjugates. Two groups of patients could be distinguished - low and high excretors, who displayed alternative routes of metabolism. The disappearance rate of AMT from plasma was determined by the metabolic clearance of AMT to its metabolites. It varied considerably between patients.

The metabolism of amitriptyline (AMT) has been studied in two groups of depressed in-patients on long term AMT therapy: 11 patients with no other major disease and 8 patients with chronic renal failure, who were being dialysed. The patients with renal insufficiency had decreased concentrations of AMT, nortriptyline (NT) and their unconjugated hydroxymetabolites compared to patients with normal kidney function. The plasma levels of conjugated products were extremely high in the uraemics. The latter metabolites are probably inert. The reduced concentration of unconjugated hydroxymetabolites , which are active compounds, may decrease the clinical effectiveness of the drug.

Our study shows, for the first time, that omeprazole infusion was significantly superior to all other regimens by having a high median pH >6 on each day. The tolerance effect of ranitidine, however, led to a rapid loss of antisecretory activity on days 2 and 3, rendering it inappropriate for situations in which high intragastric pH-levels appear to be essential.