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 (<25%), but no inhibitions were on CYP1A2- and CYP3A4-catalyzed reactions. TCAs inhibited the formation of p-hydroxyphenytoin in cDNA-expressed CYP2C9 and CYP2C19 (20-70% of control). In conclusion, TCAs appear to have a potential to increase the serum concentration of PHT coadministered through the inhibition of CYP2C9- and CYP2C19-catalyzed phenytoin p-hydroxylation.

Original languageEnglish (US)
Pages (from-to)P78
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - Dec 1 2001

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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