Pharmacokinetics of amitriptyline demethylation; a crossover study with single doses of amitriptyline and nortriptyline

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