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 phenytoinp-hydroxylation in microsomal incubations (estimatedKi 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 phenytoinp-hydroxylation, whereas TCAs inhibited only the CYP2C19 pathway. All of the TCAs tested inhibited CYP2D6-catalyzed dextromethorphan-O-demethylation competitively, with estimated Ki values of 31.0, 28.6, 7.9, and 12.5 μM, respectively. The tertiary amine TCAs, amitriptyline and imipramine, also inhibited CYP2C19-catalyzedS-mephenytoin 4′-hydroxylation (estimatedKi of 37.7 and 56.8 μM, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC50 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 phenytoinp-hydroxylation.
Footnotes
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This study was supported in part by the Ministry of Science and Technology of the Republic of Korea and by the Korea Science and Engineering Foundation through the Biohealth Products Research Center at Inje University, Korea.
- Abbreviations used are::
- HPPH
- 5-(p-hydroxyphenyl)-5-phenylhydantoin
- TCA
- tricyclic antidepressants
- G-6-P
- glucose 6-phosphate
- G-6-PDH
- glucose 6-phosphate dehydrogenase
- HPLC
- high-performance liquid chromatography
- Received January 1, 2002.
- Accepted July 2, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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