title: Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin.
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 micro M, 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 micro M, 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 micro M, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC(50) of 600 and 685 micro M, 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.
authors.affiliation: Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Busan Paik Hospital, Busan, Seoul, Korea. phsinjg@ijnc.inje.ac.kr
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
authors.forename: In-June
authors.initials: IJ
authors.lastname: Cha
authors.forename: Sang-Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: Se-Wook
authors.initials: SW
authors.lastname: Oh
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010672:Phenytoin / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System