Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes

Abstract

In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S-form of which is hydroxylated by a P450IIC isozyme, was carried out before amitriptyline therapy. Metabolites were determined in 24-hour urine samples collected on treatment day 8, and the contributions of individual compounds, including the four isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline to total excretion were calculated. Formation of (-)-E-10-hydroxyamitriptyline and (-)-E-10-hydroxynortriptyline apparently depends on the activity of cytochrome P450IID6 because negative correlations existed between the log metabolic ratio of dextromethorphan and the relative quantities of these enantiomers. In contrast, correlations were positive for nortriptyline, (+)-E-10-hydroxynortriptyline, (-)-Z-10-hydroxynortriptyline, and (+)-Z-10-hydroxynortriptyline. The mephenytoin hydroxylase seems to participate in side-chain demethylation to the secondary and primary amines, because the log metabolic ratio of mephenytoin correlated negatively with the relative quantity of E-10-hydroxydidesmethylamitriptyline and positively with that of amitriptyline and its N-glucuronide.

The effects of selective serotonin reuptake inhibitors and their metabolites on S‐mephenytoin 4'‐hydroxylase activity in human liver microsomes.

“…However, in vivo and in vitro studies have shown that imipramine and amitriptyline are also metabolized by another form of P450 (CYP2C19) which also shows the genetically determined polymorphism in humans [ 15,[17][18][19][20]. Thus, both the polymorphisms of CYP2C19 and CYP2D6 are considered to contribute to the variable plasma levels of imipramine or amitriptyline in patients treated with either of those tricyclics [15].…”

Persistence of the tricyclic antidepressant drugs amitriptyline and nortriptyline in agriculture soils

“…The hydroxylated metabolites of amitriptyline and nortriptyline are excreted in the urine mainly as glucuronide conjugates. The demethylation of amitriptyline and nortriptyline is catalyzed mainly by CYP2C19 at low amitriptyline concentrations, whereas CYP3A4 may be more important at higher amitriptyline concentrations [11,18,20]. The hydroxylation of amitriptyline and nortriptyline into their active metabolite, 10-hydroxyamitriptyline and 10-hydroxynortriptyline is catalyzed mainly by CYP2D6 [11,20].…”

“…The metabolism of amitriptyline has been thoroughly investigated in mammals (including rats, mice, and humans) and fungi [14][15][16][17][18][19][20][21]. In humans, the main pathway for amitriptyline metabolism is demethylation in liver microsomes to the pharmacologically active metabolite nortriptyline [11,20].…”

Determination of amitriptyline and its main metabolites in human plasma samples using HPLC-DAD: application to the determination of metabolic ratios after single oral dose of amitriptyline

“…The demethylation of AT and NT is mainly catalyzed by CYP2C19, with the participation of other CYP enzyme forms in higher drug concentrations. 3 The formation of the E-10-hydroxy metabolites is dependent on the activity of CYP2D6, with stereospecificity to the (-)-EHAT and (-)-EHNT metabolites. 3 Therapeutic drug monitoring (TDM) in AT pharmacotherapy is usually based on the determination of plasma concentrations of AT and its main active , with an increased incidence of adverse effects when plasma levels are above 300 ng mL -1 .…”

“…3 The formation of the E-10-hydroxy metabolites is dependent on the activity of CYP2D6, with stereospecificity to the (-)-EHAT and (-)-EHNT metabolites. 3 Therapeutic drug monitoring (TDM) in AT pharmacotherapy is usually based on the determination of plasma concentrations of AT and its main active , with an increased incidence of adverse effects when plasma levels are above 300 ng mL -1 . 4,5 Additional information can be obtained through the determination of the hydroxylated metabolites of AT and NT, once these metabolites are correlated with important clinical findings.…”