Selective Serotonin Reuptake Inhibitors and Cytochrome P-450 Mediated Drug-Drug Interactions: An Update

Abstract

The selective serotonin reuptake inhibitors (SSRIs) have become the most prescribed antidepressants in many countries. Although the SSRIs share a common mechanism of action, they differ substantially in their chemical structure, metabolism, and pharmacokinetics. Perhaps the most important difference between the SSRIs is their potential to cause drug-drug interactions through inhibition of cytochrome-P450 (CYP) isoforms. This paper provides an update on both the in vitro and in vivo evidence with respect to CYP-mediated drug-drug interactions with this class of antidepressants. The available evidence clearly indicates that the individual SSRIs display a distinct profile of cytochrome P450 inhibition. Fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor, and a moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor. Fluoxetine and paroxetine are potent CYP2D6 inhibitors, whereas fluoxetine's main metabolite, norfluoxetine, has a moderate inhibitory effect on CYP3A4. Sertraline is a moderate CYP2D6 inhibitor; citalopram appears to have little effect on the major CYP isoforms. Fluoxetine deserves special attention as inhibitory effects on CYP-activity can persist for several weeks after fluoxetine discontinuation because of the long half-life of fluoxetine and its metabolite norfluoxetine. Drug combinations with SSRIs should be assessed on an individual basis. Knowledge regarding the CYP-isoforms involved in the metabolism of the co-administered drug may help clinicians to anticipate and avoid potentially dangerous drug-drug interactions. Anticipated interactions can usually be managed by appropriate dose adjustment and titration of the object drug. In some cases, therapeutic drug monitoring can be useful. Equally well, an SSRI with limited interaction potential may be selected to treat depression in patients that receive other medications.

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

“…Support for the transport hypothesis comes from studies showing that blockade of SERT by pretreatment with the selective 5-HT reuptake inhibitor (SSRI) fluoxetine completely blocked MDMA-induced serotonergic deficits assessed shortly after drug treatments without modifying the hyperthermic response to MDMA (Malberg et al, 1996;Sanchez et al, 2001;Schmidt, 1987). However, interpretation of these findings is confounded by the fact that fluoxetine is a potent inhibitor of cytochrome P450 (CYP) isozymes that are important for MDMA metabolism (de la Torre et al, 2004;Hemeryck and Belpaire, 2002). Indeed, it is interesting to note that pretreatment with citalopram, the currently available SSRI that is most selective for SERT and that has the least effect on CYP activity (Hemeryck and Belpaire, 2002) attenuated but did not completely prevent MDMA neurotoxicity .…”

“…However, interpretation of these findings is confounded by the fact that fluoxetine is a potent inhibitor of cytochrome P450 (CYP) isozymes that are important for MDMA metabolism (de la Torre et al, 2004;Hemeryck and Belpaire, 2002). Indeed, it is interesting to note that pretreatment with citalopram, the currently available SSRI that is most selective for SERT and that has the least effect on CYP activity (Hemeryck and Belpaire, 2002) attenuated but did not completely prevent MDMA neurotoxicity .…”

“…Our objectives were to determine whether (1) access to SERT is necessary for MDMA-induced neurotoxicity using a more selective SSRI than in most previous studies, (2) the acute physiological responses to MDMA are inhibited by SSRI pretreatment, and (3) later behavioral alterations produced by MDMA are similarly prevented by SERT blockade. These objectives were accomplished by testing the effects of pretreatment with citalopram, an SSRI with a limited inhibitory effect on liver cytochrome P450 enzymes (Hemeryck and Belpaire, 2002), on the physiological, behavioral, and neurochemical responses of MDMA-exposed rats measured over a 10-week period.…”

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

“…Fluoxetine's metabolism involves the Cytochrome P450 system (Figure 1), and a combination of drugs which are also metabolised by CYPs may lead to drug interactions, even if fluoxetine has been discontinued for 4-5 weeks [55,[57][58][59][60][61].…”

The pharmacogenomics of selective serotonin reuptake inhibitors

“…Fluoxetine deserves special attention as inhibitory effects on CYP activity can persist for several weeks after fluoxetine discontinuation because of the long half-life of fluoxetine and its metabolite norfluoxetine. 114 Application of molecular genetic techniques resulted in the cloning of a complementary DNA (cDNA) and the gene Also CYP2C19 show genetic polymorphisms and the differences in phenotype between people carrying the different isoforms allowed to make a distinction between individuals with a normal catalytic function, the so-called extensive metabolisers, and a group of individuals with a severely impaired catalytic capacity, so-called poor metabolises (PM). 115,116 The CYP2D6 PM phenotype occurs at a frequency of approximately 5-10% in the Caucasian population, while it is much rarer in Black Americans and in Orientals.…”