Amitriptyline metabolism: Association with debrisoquin hydroxylation in nonsmokers

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 < 0.01) with all three parameters of amitryptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with r s = − 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. Clinical Pharmacology and Therapeutics (1986) 39, 369–371; doi: 10.1038/clpt.1986.56