Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: Mechanism of drug interaction between TCAs and phenytoin

Jae Gook Shin, Ji Young Park, Min Jung Kim, Ji Hong Shon, Young Ran Yoon, In June Cha, Sang Seop Lee, Se Wook Oh, Sang Woo Kim, David A. Flockhart

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Abstract

The ability of tricyclic antidepressants (TCAs) to inhibit phenytoin p-hydroxylation was evaluated in vitro by incubation studies of human liver microsomes and cDNA-expressed cytochrome P450s (P450s). The TCAs tested were amitriptyline, imipramine, nortriptyline, and desipramine. Amitriptyline and imipramine strongly and competitively inhibited phenytoin p-hydroxylation in microsomal incubations (estimated K i values of 5.2 and 15.5 μM, respectively). In contrast, nortriptyline and desipramine produced only weak inhibition. In the incubation study using cDNA-expressed P450s, both CYP2C9 and CYP2C19 catalyzed phenytoin p-hydroxylation, whereas TCAs inhibited only the CYP2C19 pathway. All of the TCAs tested inhibited CYP2D6-catalyzed dextromethorphan-O-demethylation competitively, with estimated K i values of 31.0, 28.6, 7.9, and 12.5 μM, respectively. The tertiary amine TCAs, amitriptyline and imipramine, also inhibited CYP2C19-catalyzed S-mephenytoin 4′-hydroxylation (estimated K i of 37.7 and 56.8 μM, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC 50 of 600 and 685 μM, respectively). None of the TCAs tested produced remarkable inhibition of any other P450 isoforms. These results suggest that TCAs inhibit both CYP2D6 and CYP2C19 and that the interaction between TCAs and phenytoin involves inhibition of CYP2C19-catalyzed phenytoin p-hydroxylation.

Original languageEnglish (US)
Pages (from-to)1102-1107
Number of pages6
JournalDrug Metabolism and Disposition
Volume30
Issue number10
DOIs
StatePublished - Oct 1 2002

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Shin, J. G., Park, J. Y., Kim, M. J., Shon, J. H., Yoon, Y. R., Cha, I. J., Lee, S. S., Oh, S. W., Kim, S. W., & Flockhart, D. A. (2002). Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: Mechanism of drug interaction between TCAs and phenytoin. Drug Metabolism and Disposition, 30(10), 1102-1107. https://doi.org/10.1124/dmd.30.10.1102