Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition

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.