Zhan Yunyun, Wang Anzhou, Yu Yige, Chen Jie, Xu Xinhao, Nie Jingjing, Lin Jingjing
Department of Pharmacy, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China.
Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Pharmacol. 2023 Sep 18;14:1199548. doi: 10.3389/fphar.2023.1199548. eCollection 2023.
Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (K) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its K values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with K values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (K = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (K = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (K = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.
伏硫西汀是一种新型抗重度抑郁症药物，与其他同类药物相比具有较高的安全性。然而，关于伏硫西汀的药物相互作用（DDI）研究较少。本文在人肝微粒体和大鼠肝微粒体中研究了伏硫西汀对细胞色素P450（CYP450）的抑制作用及其抑制机制类型。我们建立了一个200μL的孵育体系，在37℃下测定伏硫西汀存在时探针底物的代谢情况。探针底物代谢产物的浓度均采用超高效液相色谱串联质谱（UPLC-MS/MS）法测定。通过测定半数抑制浓度（IC）位移值，发现伏硫西汀不存在时间依赖性抑制（TDI）。本实验中涉及的人和大鼠的酶及代谢产物如下：CYP3A4/CYP3A（咪达唑仑）；CYP2B6/CYP2B（安非他酮）；CYP2D6/CYP2D（右美沙芬）；CYP2C8/CYP2C-1（阿莫地喹）；CYP2C9/CYP2C-2（氯沙坦）；以及CYP2C19/CYP2C-3（美芬妥英）。我们发现伏硫西汀在人肝微粒体（HLMs）中对CYP2C19和CYP2D6具有竞争性抑制作用，抑制常数（K）值分别为2.17μM和9.37μM。对CYP3A4和CYP2C8为非竞争性抑制，其K值分别为7.26μM和6.96μM。对于CYP2B6和CYP2C9，伏硫西汀表现为混合抑制，K值分别为8.55μM和4.17μM。在大鼠肝微粒体（RLMs）中，伏硫西汀对CYP3A和CYP2D的抑制类型为反竞争性抑制（K = 4.41和100.9μM）。抑制类型为竞争性抑制的包括CYP2B和CYP2C-2（K = 2.87和0.12μM）。CYP2C-1和CYP2C-3的抑制类型（K = 39.91和4.23μM）分别为混合抑制和非竞争性抑制。上述机制的研究将为伏硫西汀的安全临床应用提供指导，从而避免药物相互作用的发生。
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