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

Research output: Contribution to journalArticle

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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 2002
Externally publishedYes

Fingerprint

Drug interactions
Tricyclic Antidepressive Agents
Phenytoin
Drug Interactions
Cytochrome P-450 Enzyme System
Hydroxylation
Nortriptyline
Desipramine
Amitriptyline
Imipramine
Cytochrome P-450 CYP2D6
Amines
Complementary DNA
Mephenytoin
Dextromethorphan
In Vitro Techniques
Liver Microsomes
Cytochromes
Liver
Cytochrome P-450 CYP2C19

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro : Mechanism of drug interaction between TCAs and phenytoin. / Shin, Jae Gook; Park, Ji Young; Kim, Min Jung; Shon, Ji Hong; Yoon, Young Ran; Cha, In June; Lee, Sang Seop; Oh, Se Wook; Kim, Sang Woo; Flockhart, David A.

In: Drug Metabolism and Disposition, Vol. 30, No. 10, 10.2002, p. 1102-1107.

Research output: Contribution to journalArticle

Shin, Jae Gook ; Park, Ji Young ; Kim, Min Jung ; Shon, Ji Hong ; Yoon, Young Ran ; Cha, In June ; Lee, Sang Seop ; Oh, Se Wook ; Kim, Sang Woo ; Flockhart, David A. / Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro : Mechanism of drug interaction between TCAs and phenytoin. In: Drug Metabolism and Disposition. 2002 ; Vol. 30, No. 10. pp. 1102-1107.
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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.",
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T1 - Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro

T2 - Mechanism of drug interaction between TCAs and phenytoin

AU - Shin, Jae Gook

AU - Park, Ji Young

AU - Kim, Min Jung

AU - Shon, Ji Hong

AU - Yoon, Young Ran

AU - Cha, In June

AU - Lee, Sang Seop

AU - Oh, Se Wook

AU - Kim, Sang Woo

AU - Flockhart, David A.

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N2 - 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.

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