In vitro inhibition of tricyclic antidepressants (TCAs) on phenytoin P-hydroxylation: Involvement of CYP2C9 and CYP2C19

J. Y. Park, J. H. Shon, M. J. Kim, I. J. Cha, D. A. Flockhart, J. G. Shin

Research output: Contribution to journalArticle

Abstract

Two case reports have been described that imipramine, a TCA, increased serum concentration of coadministered phenytoin (PHT), a substrate of CYP2C9 and CYP2C19. To understand the mechanism of this interaction, we assessed the in vitro inhibition of TCAs (imipramine, desipramine, amitriptyline, and nortriptyline) on phenytoin p-hydroxylation and probe metabolic pathways of each CYP isoform using the incubation study of human liver microsomes and cDNA-expressed cytochrome P450s. Imipramine and amitriptyline competitively and strongly inhibited PHT p-hydroxylation with the estimated Ki of 6.5±2.6 μM and 2.2±0.2 μM, respectively. The inhibitory effects of desipramine and nortriptyline were weaker than those of their parent drugs (up to 11-19% of control at highest concentration). All TCAs strongly inhibited CYP2D6-catalyzed dextromethorphan O-demethylation (Ki=8-30 (J-M). Imipramine and amitriptyline slightly inhibited CYP2C9-catalyzed tolbutamide 4-methylhydroxylation and CYP2C19-catalyzed S-mephenytoin 4-hydroxylation (

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001
Externally publishedYes

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Imipramine
Tricyclic Antidepressive Agents
Phenytoin
Hydroxylation
Amitriptyline
Nortriptyline
Desipramine
Mephenytoin
Dextromethorphan
Tolbutamide
Cytochrome P-450 CYP2D6
Liver Microsomes
Cytochromes
Metabolic Networks and Pathways
Protein Isoforms
Complementary DNA
In Vitro Techniques
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Serum

ASJC Scopus subject areas

  • Pharmacology

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In vitro inhibition of tricyclic antidepressants (TCAs) on phenytoin P-hydroxylation : Involvement of CYP2C9 and CYP2C19. / Park, J. Y.; Shon, J. H.; Kim, M. J.; Cha, I. J.; Flockhart, D. A.; Shin, J. G.

In: Clinical Pharmacology and Therapeutics, Vol. 69, No. 2, 2001.

Research output: Contribution to journalArticle

Park, J. Y. ; Shon, J. H. ; Kim, M. J. ; Cha, I. J. ; Flockhart, D. A. ; Shin, J. G. / In vitro inhibition of tricyclic antidepressants (TCAs) on phenytoin P-hydroxylation : Involvement of CYP2C9 and CYP2C19. In: Clinical Pharmacology and Therapeutics. 2001 ; Vol. 69, No. 2.
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