Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Effects of Dietary Flavonoids on the Metabolism of Vortioxetine and its Potential Mechanism

Author(s): Yuxian Lin, Yu Wang, Zhize Ye, Nanyong Gao, Xinhao Xu, Qinghua Weng, Ren-ai Xu* and Lei Ye*

Volume 31, Issue 23, 2024

Published on: 07 July, 2023

Page: [3624 - 3630] Pages: 7

DOI: 10.2174/0929867330666230607104411

Price: $65

conference banner
Abstract

Introduction: Quercetin and apigenin are two common dietary flavonoids widely found in foods and fruits. Quercetin and apigenin can act as the inhibitors of CYP450 enzymes, which may affect the pharmacokinetics of clinical drugs. Vortioxetine (VOR), approved for marketing by the Food and Drug Administration (FDA) in 2013, is a novel clinical drug for treating major depressive disorder (MDD).

Objective: This study aimed to evaluate the effects of quercetin and apigenin on the metabolism of VOR in in vivo and in vitro experiments.

Methods: Firstly, 18 Sprague-Dawley rats were randomly divided into three groups: control group (VOR), group A (VOR + 30 mg/kg quercetin) and group B (VOR + 20 mg/kg apigenin). We collected the blood samples at different time points before and after the final oral administration of 2 mg/kg VOR. Subsequently, we further used rat liver microsomes (RLMs) to investigate the half-maximal inhibitory concentration (IC50) of the metabolism of vortioxetine. Finally, we evaluated the inhibitory mechanism of two dietary flavonoids on VOR metabolism in RLMs.

Results: In animal experiments, we found AUC (0-∞) (area under the curve from 0 to infinity) and CLz/F (clearance) to be obviously changed. Compared to controls, AUC (0-∞) of VOR in group A and group B was 2.22 and 3.54 times higher, respectively, while CLz/F of VOR in group A and group B was significantly decreased down to nearly two-fifth and one-third. In in vitro studies, the IC50 value of quercetin and apigenin in the metabolic rate of vortioxetine was 5.323 μM and 3.319 μM, respectively. Ki value of quercetin and apigenin was found to be 0.040 and 3.286, respectively, and the αKi value of quercetin and apigenin was 0.170 and 2.876 μM, respectively.

Conclusion: Quercetin and apigenin exhibited inhibitory effects on the metabolism of vortioxetine in vivo and in vitro. Moreover, quercetin and apigenin had a mixed mechanism on the metabolism of VOR in RLMs. Thus, we should pay more attention to the combination between these dietary flavonoids and VOR in the future clinical use.

Keywords: Quercetin, apigenin, vortioxetine, metabolism, rats, pharmacokinetics.

« Previous Next »
[1]
Lu, J.; Xu, X.; Huang, Y.; Li, T.; Ma, C.; Xu, G.; Yin, H.; Xu, X.; Ma, Y.; Wang, L.; Huang, Z.; Yan, Y.; Wang, B.; Xiao, S.; Zhou, L.; Li, L.; Zhang, Y.; Chen, H.; Zhang, T.; Yan, J.; Ding, H.; Yu, Y.; Kou, C.; Shen, Z.; Jiang, L.; Wang, Z.; Sun, X.; Xu, Y.; He, Y.; Guo, W.; Jiang, L.; Li, S.; Pan, W.; Wu, Y.; Li, G.; Jia, F.; Shi, J.; Shen, Z.; Zhang, N. Prevalence of depressive disorders and treatment in China: A cross-sectional epidemiological study. Lancet Psychiatry, 2021, 8(11), 981-990.
[http://dx.doi.org/10.1016/S2215-0366(21)00251-0] [PMID: 34559991]
[2]
Dhir, A. Vortioxetine for the treatment of major depression. Drugs Today , 2013, 49(12), 781-790.
[http://dx.doi.org/10.1358/dot.2013.49.12.2058448] [PMID: 24524096]
[3]
Hvenegaard, M.G.; Bang-Andersen, B.; Pedersen, H.; Jørgensen, M.; Püschl, A.; Dalgaard, L. Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. Drug Metab. Dispos., 2012, 40(7), 1357-1365.
[http://dx.doi.org/10.1124/dmd.112.044610] [PMID: 22496396]
[4]
Xu, R.; Luo, S.; Lin, Q.; Shao, Y.; Chen, C.; Ye, X. Inhibitory effect of propafenone on vortioxetine metabolism in vitro and in vivo. Arab. J. Chem., 2021, 14(5), 103136.
[http://dx.doi.org/10.1016/j.arabjc.2021.103136]
[5]
Vissenaekens, H.; Grootaert, C.; Raes, K.; De Munck, J.; Smagghe, G.; Boon, N.; Van Camp, J. Quercetin mitigates endothelial activation in a novel intestinal-endothelialmonocyte/macrophage coculture setup. Inflammation, 2022, 45(4), 1600-1611.
[http://dx.doi.org/10.1007/s10753-022-01645-w] [PMID: 35352237]
[6]
Al-Khayri, J.M.; Sahana, G.R.; Nagella, P.; Joseph, B.V.; Alessa, F.M.; Al-Mssallem, M.Q. Flavonoids as potential anti-inflammatory molecules: A review. Molecules, 2022, 27(9), 2901.
[http://dx.doi.org/10.3390/molecules27092901] [PMID: 35566252]
[7]
Sang, A.; Wang, Y.; Wang, S.; Wang, Q.; Wang, X.; Li, X.; Song, X. Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways. Cell. Signal., 2022, 96, 110363.
[http://dx.doi.org/10.1016/j.cellsig.2022.110363] [PMID: 35644425]
[8]
Cui, Z.; Zhao, X.; Amevor, F.K.; Du, X.; Wang, Y.; Li, D.; Shu, G.; Tian, Y.; Zhao, X. Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism. Front. Immunol., 2022, 13, 943321.
[http://dx.doi.org/10.3389/fimmu.2022.943321] [PMID: 35935939]
[9]
Kuru Bektaşoğlu, P.; Demir, D.; Koyuncuoğlu, T.; Yüksel, M.; Peker Eyüboğlu, İ.; Karagöz Köroğlu, A.; Akakın, D.; Yıldırım, A.; Çelikoğlu, E.; Gürer, B. Possible anti-inflammatory, antioxidant, and neuroprotective effects of apigenin in the setting of mild traumatic brain injury: An investigation. Immunopharmacol. Immunotoxicol., 2022, 2022, 1-12.
[http://dx.doi.org/10.1080/08923973.2022.2130076] [PMID: 36168996]
[10]
Zhou, Y.; Hua, A.; Zhou, Q.; Geng, P.; Chen, F.; Yan, L.; Wang, S.; Wen, C. Inhibitory effect of Lygodium root on the cytochrome P450 3A enzyme in vitro and in vivo. Drug Des. Devel. Ther., 2020, 14, 1909-1919.
[http://dx.doi.org/10.2147/DDDT.S249308] [PMID: 32546958]
[11]
Rastogi, H.; Jana, S. Evaluation of inhibitory effects of caffeic acid and quercetin on human liver cytochrome p450 activities. Phytother. Res., 2014, 28(12), 1873-1878.
[http://dx.doi.org/10.1002/ptr.5220] [PMID: 25196644]
[12]
Gu, E-M.; Shao, Y.; Xu, W-F.; Ye, L.; Xu, R. UPLC-MS/MS for simultaneous quantification of vortioxetine and its metabolite Lu AA34443 in rat plasma and its application to drug interactions. Arab. J. Chem., 2020, 13(11), 8218-8225.
[http://dx.doi.org/10.1016/j.arabjc.2020.09.056]
[13]
He, J.; Fang, P.; Zheng, X.; Wang, C.; Liu, T.; Zhang, B.; Wen, J.; Xu, R. Inhibitory effect of celecoxib on agomelatine metabolism in vitro and in vivo. Drug Des. Devel. Ther., 2018, 12, 513-519.
[http://dx.doi.org/10.2147/DDDT.S160316] [PMID: 29563776]
[14]
Huang, Y.; Zheng, S.; Pan, Y.; Li, T.; Xu, Z.; Shao, M. Simultaneous quantification of vortioxetine, carvedilol and its active metabolite 4-hydroxyphenyl carvedilol in rat plasma by UPLC–MS/MS: Application to their pharmacokinetic interaction study. J. Pharm. Biomed. Anal., 2016, 128, 184-190.
[http://dx.doi.org/10.1016/j.jpba.2016.05.029] [PMID: 27262994]
[15]
Chen, G.; Lee, R.; Højer, A.M.; Buchbjerg, J.K.; Serenko, M.; Zhao, Z. Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin. Drug Investig., 2013, 33(10), 727-736.
[http://dx.doi.org/10.1007/s40261-013-0117-6] [PMID: 23975654]
[16]
Zhang, Y.; Liu, Y.; Xie, S.; Xu, X.; Xu, R. Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC–MS/MS assay. Pharm. Biol., 2022, 60(1), 621-626.
[http://dx.doi.org/10.1080/13880209.2022.2048862] [PMID: 35289238]
[17]
Aleksandar, R.; Milica, P.K.; Gorana, M.; Boris, M.; Anastazija, S.M.; Mladena, L.P.; Snežana, S.; Nebojša, S.; Slobodan, G. Interaction between apigenin and sodium deoxycholate with raloxifene: A potential risk for clinical practice. Eur. J. Pharm. Sci., 2021, 161, 105809.
[http://dx.doi.org/10.1016/j.ejps.2021.105809] [PMID: 33741473]
[18]
Bhutani, P.; Rajanna, P.K.; Paul, A.T. Impact of quercetin on pharmacokinetics of quetiapine: Insights from in-vivo studies in wistar rats. Xenobiotica, 2020, 50(12), 1483-1489.
[http://dx.doi.org/10.1080/00498254.2020.1792002] [PMID: 32623931]
[19]
Elbarbry, F.; Ung, A.; Abdelkawy, K. Studying the inhibitory effect of Quercetin and Thymoquinone on human cytochrome P450 enzyme activities. Pharmacogn. Mag., 2018, 13(Suppl. 4), S895-S899.
[http://dx.doi.org/10.4103/0973-1296.224342] [PMID: 29491651]
[20]
Vijayakumar, T.M.; Kumar, R.M.; Agrawal, A.; Dubey, G.P.; Ilango, K. Comparative inhibitory potential of selected dietary bioactive polyphenols, phytosterols on CYP3A4 and CYP2D6 with fluorometric high-throughput screening. J. Food Sci. Technol., 2015, 52(7), 4537-4543.
[http://dx.doi.org/10.1007/s13197-014-1472-x] [PMID: 26139922]
[21]
Kondža, M.; Bojić, M.; Tomić, I.; Maleš, Ž.; Rezić, V.; Ćavar, I. Characterization of the CYP3A4 enzyme inhibition potential of selected flavonoids. Molecules, 2021, 26(10), 3018.
[http://dx.doi.org/10.3390/molecules26103018] [PMID: 34069400]
[22]
Zhao, Q.; Wei, J.; Zhang, H. Effects of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. Xenobiotica, 2019, 49(5), 563-568.
[http://dx.doi.org/10.1080/00498254.2018.1478168] [PMID: 29768080]

Rights & Permissions Print Cite
Article Metrics
25
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy