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

  • Authors: Lin Y.1, Wang Y.2, Ye Z.3, Gao N.4, Xu X.5, Weng Q.6, Xu R.7, Ye L.8
  • Affiliations:
    1. Department of Pharmacy,, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), The Third Clinical Institute Affiliated to Wenzhou Medical University
    2. Basic Medicine College,, Renji College of Wenzhou Medical University
    3. School of Pharmaceutical Sciences, Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University
    4. School of Pharmaceutical Sciences, Institute of Molecular Toxicology and Pharmacology,, Wenzhou Medical University
    5. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University
    6. Department of Pharmacy,, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), The Third Clinical Institute Affiliated to Wenzhou Medical University,
    7. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,, The First Affiliated Hospital of Wenzhou Medical University
    8. Procurement Department, The First Affiliated Hospital of Wenzhou Medical University
  • Issue: Vol 31, No 23 (2024)
  • Pages: 3624-3630
  • Section: Anti-Infectives and Infectious Diseases
  • URL: https://gynecology.orscience.ru/0929-8673/article/view/645225
  • DOI: https://doi.org/10.2174/0929867330666230607104411
  • ID: 645225

Cite item

Full Text

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.

Method: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.

About the authors

Yuxian Lin

Department of Pharmacy,, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), The Third Clinical Institute Affiliated to Wenzhou Medical University

Email: info@benthamscience.net

Yu Wang

Basic Medicine College,, Renji College of Wenzhou Medical University

Email: info@benthamscience.net

Zhize Ye

School of Pharmaceutical Sciences, Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University

Email: info@benthamscience.net

Nanyong Gao

School of Pharmaceutical Sciences, Institute of Molecular Toxicology and Pharmacology,, Wenzhou Medical University

Email: info@benthamscience.net

Xinhao Xu

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University

Email: info@benthamscience.net

Qinghua Weng

Department of Pharmacy,, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), The Third Clinical Institute Affiliated to Wenzhou Medical University,

Email: info@benthamscience.net

Ren-ai Xu

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,, The First Affiliated Hospital of Wenzhou Medical University

Author for correspondence.
Email: info@benthamscience.net

Lei Ye

Procurement Department, The First Affiliated Hospital of Wenzhou Medical University

Author for correspondence.
Email: info@benthamscience.net

References

  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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1080/00498254.2018.1478168 PMID: 29768080

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers