A single dose crossover pharmacokinetic study of amitriptyline and nortriptyline
was done to find out the extent of first-pass metabolism to nortriptyline after amitripyline
administration, and the contribution of nortriptyline during amitriptyline therapy. Six healthy
male volunteers took part in this study and were given single doses (50 mg) of amitriptyline
and nortriptyline at more than three-week intervals. Plasma concentrations of the drugs were
measured up to 48 hours. Total area under the plasma concentration-time curve (AUe) of
amitriptyline (744.6±258.4 ng/ml·hl was smaller than that of nortriptyline (l497.3±589.8
ng/ml'h), and the mean terminal half-life of amitriptyline (21.8±3.9 hr) was shorter than
that of nortriptyline (36.8±5.9 h). The total area under the plasma concentration-time curve
of nortriptyline produced by amitriptyline administration was 498.1 ±274.5 ng/ml·h, and the
fraction produced by the first-pass of amitriptyline was 33.7 ± 10.5%.
From this data, it can be estimated that the average nortriptyline concentration could be
about 40% of the total tricyclic antidepressants present in the plasma of patients taking
multiple amitriptyline therapy at steady state. About 34% of nortriptyline is produced by
first- pass effect during gastrointestinal absorption of amitriptyline to systemic circulation resulting
from N-demethylation of amitriptyline in the liver. Then, the rest of the nortriptyline is
formed continuously at a rate proportional to the rate of amitriptyline elimination
