Hemeryck Alex, Belpaire Frans M
Heymans Institute of Pharmacology, Ghent University, Faculty of Medicine and Health Sciences, Belgium.
Curr Drug Metab. 2002 Feb;3(1):13-37. doi: 10.2174/1389200023338017.
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.
在许多国家，选择性5-羟色胺再摄取抑制剂（SSRI）已成为处方量最多的抗抑郁药。尽管SSRI具有共同的作用机制，但它们在化学结构、代谢及药代动力学方面却有很大差异。或许，SSRI之间最重要的区别在于它们通过抑制细胞色素P450（CYP）同工酶引发药物相互作用的可能性。本文就CYP介导的此类抗抑郁药药物相互作用的体外和体内证据提供了最新信息。现有证据清楚表明，各个SSRI对细胞色素P450的抑制作用表现出不同特征。氟伏沙明是一种强效CYP1A2和CYP2C19抑制剂，也是一种中度CYP2C9、CYP2D6和CYP3A4抑制剂。氟西汀和帕罗西汀是强效CYP2D6抑制剂，而氟西汀的主要代谢产物去甲氟西汀对CYP3A4有中度抑制作用。舍曲林是一种中度CYP2D6抑制剂；西酞普兰似乎对主要的CYP同工酶影响很小。氟西汀值得特别关注，因为由于氟西汀及其代谢产物去甲氟西汀半衰期长，其对CYP活性的抑制作用在停药后可持续数周。与SSRI的药物组合应逐个进行评估。了解共同给药药物代谢中涉及的CYP同工酶，可能有助于临床医生预测并避免潜在的危险药物相互作用。预期的相互作用通常可通过适当调整目标药物剂量和滴定来处理。在某些情况下，治疗药物监测可能有用。同样，对于正在接受其他药物治疗的患者，可选择相互作用潜力有限的SSRI来治疗抑郁症。
