Deodhar Malavika, Rihani Sweilem B Al, Darakjian Lucy, Turgeon Jacques, Michaud Veronique
Precision Pharmacotherapy Research and Development Institute, Tabula Rasa Health Care, Lake Nona, Orlando, FL 32827, USA.
Faculty of pharmacy, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Pharmaceutics. 2021 Jan 23;13(2):148. doi: 10.3390/pharmaceutics13020148.
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.
氟西汀仍然是世界上使用最广泛的抗抑郁药之一。该药物通过多种细胞色素P450（CYP450）酶进行广泛代谢，并会发生大量由CYP450介导的药物相互作用。在多药治疗方案中，要预先减轻药物相互作用，就需要了解氟西汀对这些CYP450酶的作用。氟西汀生成其活性代谢产物去甲氟西汀的主要代谢途径由CYP2D6介导。氟西汀和去甲氟西汀是CYP2D6的强亲和力底物，可能通过多种机制抑制其他敏感的CYP2D6底物的代谢。值得注意的是，氟西汀介导的CYP2D6抑制作用在氟西汀首次通过肝脏很久之后才会消退，甚至在停药后仍会持续很长时间。在此，我们综述药代动力学和药物遗传学信息，以帮助我们理解氟西汀给药后CYP2D6受到长期抑制的潜在机制。我们认为，CYP2D6的长期抑制可能是竞争性抑制的结果。这是由于氟西汀和去甲氟西汀与该酶的强亲和力结合，以及它们消除半衰期长，导致血液中未结合的氟西汀和去甲氟西汀水平长时间循环。此外，我们还描述了氟西汀是CYP2C9的底物和CYP2C19的基于机制的抑制剂。
