Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers

Clin Pharmacol Ther. 1986 Apr;39(4):369-71. doi: 10.1038/clpt.1986.56.


Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Amitriptyline / blood
  • Amitriptyline / metabolism*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2D6
  • Debrisoquin / analogs & derivatives
  • Debrisoquin / metabolism
  • Debrisoquin / urine
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Hydroxylation
  • Kinetics
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Mixed Function Oxygenases / metabolism*
  • Nortriptyline / blood
  • Nortriptyline / metabolism*
  • Phenotype


  • Amitriptyline
  • 4-hydroxydebrisoquin
  • Nortriptyline
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2D6
  • Debrisoquin