The Seolll [ouma! (!{ Medicine

V"I. 31, N". 1: II-IX, Marcil 1990

Pharmacokinetics of Amitriptyline Demethylation;

A Crossover Study with Single Doses of Amitriptyline and

Nortriptyline1

In-Jin Jang, Jae-Gook Shin, Sang-Goo Shin,2 Chan-Woong Park,

Jae-Jin Kim', Jong-In Woo' and In-Jun Chao,

Clinical PJldrmaco!o,fIY Unit, Seoul National University Hospital and Department ~f Phamlt1Colo,~y and

Psychiatry*, Sl'oHI National University College of Medicine

Seoul 110-460, Korea

Department of Pharmaco!o,ey**, 111)(' University College (?f Medicine

PI/SIIII 614-110, Korea

= 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 amitripylineadministration, and the contribution of nortriptyline during amitriptyline therapy. Six healthymale volunteers took part in this study and were given single doses (50 mg) of amitriptylineand nortriptyline at more than three-week intervals. Plasma concentrations of the drugs weremeasured up to 48 hours. Total area under the plasma concentration-time curve (AUe) ofamitriptyline (744.6±258.4 ng/ml·hl was smaller than that of nortriptyline (l497.3±589.8ng/ml'h), and the mean terminal half-life of amitriptyline (21.8±3.9 hr) was shorter thanthat of nortriptyline (36.8±5.9 h). The total area under the plasma concentration-time curveof nortriptyline produced by amitriptyline administration was 498.1 ±274.5 ng/ml·h, and thefraction 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 beabout 40% of the total tricyclic antidepressants present in the plasma of patients takingmultiple amitriptyline therapy at steady state. About 34% of nortriptyline is produced byfirst- 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 isformed continuously at a rate proportional to the rate of amitriptyline elimination.

Key Words: Amitriptyline. Nortriptyline, First-pass effect, N-demethylation. Phannacokinetics

Received ;)/2/90: re-vised 2fV:Y90: accepted :)/:L/90

l . This study was supported by the grant from theBasic Research Promotion Fund of Collom- ofMedic-inc. Seoul Nat ronal University (1989)

') Author for correspondence.

INTRODUCTION

For the treatment of primary unipolar depress­Ion, the clinical response of tricyclic antidepress­ant IS reported to be less than 70%(Bennett.1967). The casuses of modest efficacy of thedrugs are thought to be due to the biochemicaldifferences of patnophvsroloqv. low complianceof the depressed patients and pharrnacokinetic