Pharmacology

Original Papers

Metabolism of the Tricyclic Antidepressant Amitriptyline by cDNA-Expressed Human Cytochrome P450 Enzymes

Olesen O.V. · Linnet K.

Author affiliations

Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Risskov, Denmark

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Pharmacology 1997;55:235–243

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Article / Publication Details

First-Page Preview
Abstract of Original Papers

Received: March 21, 1997
Accepted: June 30, 1997
Published online: June 10, 2008
Issue release date: 1997

Number of Print Pages: 9
Number of Figures: 0
Number of Tables: 0

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: https://www.karger.com/PHA

Abstract

The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)-10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with Km values in the range of 5-13 µmol/l, whereas the affinities of 1 A2, 3A4 and 2C9 were somewhat lower with Km values ranging from 74 to 92 µmol/l. CYP 2C19 displayed the highest reaction capacity per mole with Vmax equal to 475 mol h–1 (mol CYP)–1. The other enzymes had Vmax values in the range of 90–145 mol h–1 (mol CYP)–1. Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the metabolism.

© 1997 S. Karger AG, Basel




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Article / Publication Details

First-Page Preview
Abstract of Original Papers

Received: March 21, 1997
Accepted: June 30, 1997
Published online: June 10, 2008
Issue release date: 1997

Number of Print Pages: 9
Number of Figures: 0
Number of Tables: 0

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: https://www.karger.com/PHA


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