RT Journal Article
SR Electronic
T1 Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1102
OP 1107
DO 10.1124/dmd.30.10.1102
VO 30
IS 10
A1 Shin, Jae-Gook
A1 Park, Ji-Young
A1 Kim, Min-Jung
A1 Shon, Ji-Hong
A1 Yoon, Young-Ran
A1 Cha, In-June
A1 Lee, Sang-Seop
A1 Oh, Se-Wook
A1 Kim, Sang-Woo
A1 Flockhart, David A.
YR 2002
UL http://dmd.aspetjournals.org/content/30/10/1102.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics