Pharmacokinetics of Amitriptyline Demethylation;A Crossover Study with Single Doses of Amitriptyline and Nortriptyline

Abstract

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.