The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine

Erik Skjelbo*, Kim Brøsen, Jesper Hallas, Lars F. Gram

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The metabolism of imipramine in six poor metabolizers of mephenytoin was compared with the metabolism of 16 extensive metabolizers of mephenytoin from an earlier study. Each subject was given single doses of 100 mg imipramine hydrochloride and 100 mg desipramine hydrochloride on separate occasions. Imipramine demethylation clearance was 0.74 L · min-1 (mean; range, 0.31 - 1.24) in poor metabolizers of mephenytoin compared with 1.43 L · min-1 (mean; range, 0.61 - 3.81) in extensive metabolizers of mephenytoin (p = 0.01, Mann-Whitney U test). It has previously been shown that the imipramine clearance by way of other pathways and desipramine oral clearance, both largely representing 2-hydroxylation, are considerably lower in poor metabolizers of sparteine than in extensive metabolizers of sparteine. In contrast, five subjects who were poor metabohzers of mephenytoin and extensive metabolizers of sparteine and a control group of 11 subjects who were extensive metabolizers of mephenytoin and sparteine showed no statistically significant difference with regard to these parameters. One subject who was a poor metabolizer of mephenytoin and sparteine had the lowest imipramine oral clearance of all 22 subjects studied In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2-hydroxylation by way of the sparteine oxygenase (P450IID6) and demethylation by way of the mephenytoin oxygenase (P450IIC8).

Original languageEnglish
JournalClinical Pharmacology and Therapeutics
Volume49
Issue number1
Pages (from-to)18-23
Number of pages6
ISSN0009-9236
DOIs
Publication statusPublished - 1. Jan 1991

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