Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition

Abstract

Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug–drug interactions requires knowledge of fluoxetine actions on these CYP450 enzymes. The major metabolic pathway of fluoxetine leading to the formation of its active metabolite, norfluoxetine, is mediated by CYP2D6. Fluoxetine and norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit, potentially through various mechanisms, the metabolism of other sensitive CYP2D6 substrates. Remarkably, fluoxetine-mediated CYP2D6 inhibition subsides long after fluoxetine first passes through the liver and even remains long after the discontinuation of the drug. Herein, we review pharmacokinetic and pharmacogenetic information to help us understand the mechanisms underlying the prolonged inhibition of CYP2D6 following fluoxetine administration. We propose that long-term inhibition of CYP2D6 is likely a result of competitive inhibition. This is due to strong affinity binding of fluoxetine and norfluoxetine to the enzyme and unbound fluoxetine and norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life. Additionally, we describe that fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19.

Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro

“…However, the influence of remdesivir on CYP-enzyme dependent metabolism is suggested to be weak [ 61 , 63 ]. Thus, simultaneous administration with fluoxetine, another known inhibitor of CYPs (CYP2D6 and CYP2C9/10) should be carefully monitored [ 64 , 65 , 66 ]. As fluoxetine is also a serotonin-reuptake inhibitor (SRI), simultaneous administration with other SRIs should also be avoided (including amphetamines and other sympathomimetic appetite suppressants) [ 67 , 68 ].…”

Drug repurposing of selective serotonin reuptake inhibitors: Could these drugs help fight COVID-19 and save lives?

“…desipramine (50 mg) mean plasma concentrations were increased 4.4-fold when used with 20 mg fluoxetine for 20 days [119]. CYP2D6 is also known to be involved in the metabolism of opioid analgesics (e.g., tramadol and codeine), class I antiarrhythmic drugs, first-generation H1-blockers, and antipsychotic drugs (e.g., haloperidol, risperidone, clozapine, and thioridazine) [120,121]. Therefore, concomitant use of fluoxetine with any of these drugs poses a risk for potential drug-drug interactions leading to adverse effects or therapeutic failure.…”

Gliptins vs. Milk-derived Dipeptidyl-Peptidase IV Inhibiting Biopeptides: Physicochemical Characterization and Pharmacokinetic Profiling

“…As shown, BAPs were revealed to be unlikely substrates/ inhibitors to the majority of CYP450, yet only one peptide (ID 30) exhibited suitable properties for CYP2C9 inhibition. On the other hand, one peptide (ID 31) showed to be a viable substrate for CYP2D6, which is involved in the metabolic pathway of small amine-containing molecules and might explain the affinity for Ile-Trp dipeptide (ID 31) (55). Gliptins, on the contrary, reported a higher number of interactions with CYP450 enzymes compared to BAPs.…”