Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

Abstract

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 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 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 M, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC 50 of 600 and 685 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.

Drug Synergy – Mechanisms and Methods of Analysis

“…To date, 56 subtypes of cytochrome P450 are found in humans, some of which are critical in metabolism of endogenous substances such as medical drugs. Substances interfering with cytochrome P450 may, therefore, have an impact on drug clearance and thus on the actual concentration of a certain drug in the body (Flockhart 1995;Flockhart and Oesterheld 2000;Shin, Park et al 2002;Takada, Arefayene et al 2004). There are numerous internet tools that list known drug interactions.…”

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

“…5,15) Many of the psychotropic drugs, including fluoxetine (a selective serotonin reuptake inhibitor, SSRI), imipramine (a tricyclic antidepressant and a serotonin and noradrenaline reuptake inhibitor), and desipramine (a noradrenaline reuptake inhibitor), are metabolized by CYP2D and/or inhibit the CYP2D-mediated metabolic activities. 8,15,[19][20][21][22][23] One of the dopamine uptake sites in the brain displays high affinity for dopamine uptake inhibitors such as mazindol, a noradrenaline reuptake inhibitor. 24,25) The other site displays rather high affinity for piperizine derivatives and has been termed the piperazine acceptor site.…”

Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

“…Although CYP2C9, the primary enzyme that metabolizes S-WAR in humans, is not present in rats, rat CYP2C6 reportedly corresponds to CYP2C9 in humans based on the following findings 32) : 1) With regard to metabolic activity, human CYP2C9 and rat CYP2C6 both catalyze S-WAR 7-hydroxylation, diclofenac 4-hydroxylation and phenytoin 7-hydroxylation, and are selectively inhibited by sulfaphenazole. 17,[33][34][35][36][37][38][39][40] 2) With regard to expression, both human CYP2C9 and rat CYP2C6 are known to be induced by phenobarbital. 41,42) The nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), and glucocorticoid receptor (GR) play an important role in regulating the expression of human CYP2C9.…”