DEMETHYLATION AND HYDROXYLATION OF AMITRIPTYLINE, NORTRIPTYLINE, AND 10-HYDROXYAMITRIPTYLINE IN HUMAN-LIVER MICROSOMES

Abstract

The rates of demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxyamitriptyline by microsomes from adult human livers were determined by use of mass-fragmentographic or liquid-chromatographic quantitation of the formed metabolites. The demethylation rates of amitriptyline and 10-hydroxyamitriptyline were higher than the hydroxylation rates of amitriptyline and nortriptyline, especially at high substrate concentration. The amitriptyline demethylation rates were 96-570 and 1750-9230 pmol/mg of protein per 10 min at substrate concentrations of 5 and 100 .mu.M, respectively. The corresponding rates for the hydroxylations were 43-146 and 305-871. At high substrate concentration (250 .mu.M) the curve of concentration vs. rate for 10-hydroxylation of amitriptyline seemed to approach a plateau, whereas those for demethylation did not. Interaction between amitriptyline and nortriptyline at the microsomal level was studied by use of deuterium-labeled amitriptyline, and these 2 compounds inhibited the hydroxylation of each other. In contrast to hydroxylation, the demethylation of labeled amitriptyline increased on addition of nortriptyline. Apparently, the well established variation in steady-state plasma levels of tricyclic antidepressants is due to interindividual differences in liver enzyme activity.