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Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review

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Abstract

Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.

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References

  1. Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Therap. 2002;96:67–202.

    Article  CAS  Google Scholar 

  2. Mahomoodally MF, Gurib-Fakim A, Subratty AH. Antimicrobial activities and phytochemical profiles of endemic medicinal plants of Mauritius. Pharm Biol. 2005;43(3):237–42.

    Article  Google Scholar 

  3. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J. 2013.

  4. Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med. 1996;20:933–56.

    Article  CAS  PubMed  Google Scholar 

  5. Campanero MA, Escolar M, Perez G, Garcia-Quetglas E, Sadaba B, Azanza JR. Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: application to a clinical pharmacokinetic study. J Pharm Biomed Anal. 2010;51(4):875–81.

    Article  CAS  PubMed  Google Scholar 

  6. Russo R, Chandradhara D, De Tommasi N. Comparative bioavailability of two diosmin formulations after oral administration to healthy volunteers. Molecules. 2018;23(9):2174.

    Article  PubMed Central  Google Scholar 

  7. Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63:71–100.

    Article  CAS  PubMed  Google Scholar 

  8. Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations for the medical management of chronic venous disease: The role of Micronized Purified Flavanoid Fraction (MPFF): Recommendations from the Working Group in Chronic Venous Disease (CVD) 2016. Phlebology. 2017;32(1_suppl):3–19.

    Article  PubMed  Google Scholar 

  9. Maksimović ZV, Maksimović M, Jadranin D, Kuzmanović I, Andonović O. Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin–a prospective study. Acta Chir Iugosl. 2008;55(4):53–9.

    Article  PubMed  Google Scholar 

  10. Shelygin Y, Krivokapic Z, Frolov SA, Kostarev IV, Astashov VL, Vasiliev SV, et al. Clinical acceptability study of micronized purified flavonoid fraction 1000 mg tablets versus 500 mg tablets in patients suffering acute hemorrhoidal disease. Curr Med Res Opin. 2016;32(11):1821–6.

    Article  CAS  PubMed  Google Scholar 

  11. Jain D, Bansal MK, Dalvi R, Upganlawar A, Somani R. Protective effect of diosmin against diabetic neuropathy in experimental rats. J Integr Med. 2014;12(1):35–41.

    Article  PubMed  Google Scholar 

  12. Ahmed S, Mundhe N, Borgohain M, Chowdhury L, Kwatra M, Bolshette N, et al. Diosmin modulates the NF-kB signal transduction pathways and downregulation of various oxidative stress markers in alloxan-induced diabetic nephropathy. Inflammation. 2016;39(5):1783–97.

    Article  CAS  PubMed  Google Scholar 

  13. Gerges SH, Wahdan SA, Elsherbiny DA, El-Demerdash E. Diosmin ameliorates inflammation, insulin resistance, and fibrosis in an experimental model of non-alcoholic steatohepatitis in rats. Toxicol Appl Pharmacol. 2020;15:401.

    Google Scholar 

  14. Meyer OC. Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease. Angiology. 1994;45(6 Pt 2):579–84.

    Article  CAS  PubMed  Google Scholar 

  15. Söylemez H, Kiliç S, Atar M, Penbegül N, Sancaktutar AA, Bozkurt Y. Effects of micronised purified flavonoid fraction on pain, semen analysis and scrotal color Doppler parameters in patients with painful varicocele; results of a randomized placebo-controlled study. Int Urol Nephrol. 2012;44(2):401–8.

    Article  PubMed  Google Scholar 

  16. Shalkami AS, Hassan MIA, Bakr AG. Anti-inflammatory, antioxidant and anti-apoptotic activity of diosmin in acetic acid-induced ulcerative colitis. Hum Exp Toxicol. 2018;37(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  17. Arab HH, Salama SA, Omar HA, Arafa ESA, Maghrabi IA. Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One. 2015;10(3):e0122417.

    Article  Google Scholar 

  18. Srinivasan S, Pari L. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chem Biol Interact. 2012;195(1):43–51.

    Article  CAS  PubMed  Google Scholar 

  19. Hasan HF, Abdel-Rafei MK, Galal SM. Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt-β-catenin signaling. Biochem Cell Biol. 2017;95(3):400–14.

    Article  CAS  PubMed  Google Scholar 

  20. Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. Oxid Med Cell Longev. 2017;2017:3281670.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Navrátilová Z and the EDET study group. Efficacy of a 6-month treatment with Daflon 500 mg in patients with venous edema. Phlebolymphology. 2010;17(3):137–43.

  22. Feldo M, Woźniak M, Wójciak-Kosior M, Sowa I, Kot-Waśik A, Aszyk J, et al. Influence of diosmin treatment on the level of oxidative stress markers in patients with chronic venous insufficiency. Oxid Med Cell Longev. 2018;2018:2561705.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Garner RC, Garner JV, Gregory S, Whattam M, Calam A, Leong D. Comparison of the absorption of micronized (daflon 500® mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002;91(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  24. Patel K, Gadewar M, Tahilyani V, Patel DK. A review on pharmacological and analytical aspects of diosmetin: a concise report. Chin J Integr Med. 2013;19:792–800.

    Article  CAS  PubMed  Google Scholar 

  25. Serra H, Mendes T, Bronze M, Simplício A. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg Med Chem. 2008;16(7):4009–18.

    Article  CAS  PubMed  Google Scholar 

  26. Bhattacharyya S, Pal S, Mohamed R, Singh P, Chattopadhyay S, Pal China S, et al. A nutraceutical composition containing diosmin and hesperidin has osteogenic and anti-resorptive effects and expands the anabolic window of teriparatide. Biomed Pharmacother. 2019;1:118.

    Google Scholar 

  27. Amato C. Advantage of a micronized flavonoidic fraction (Daflon 500 mg) in comparison with a nonmicronized diosmin-PubMed. Angiology. 1994;45(6 Pt 2):531–6.

    CAS  PubMed  Google Scholar 

  28. Zhu T, Du M, Su H, Yang L. Pharmacokinetics of diosmin tablets in healthy volunteers|Request PDF. Chin J New Drugs. 2014;23(14):1674–8.

    CAS  Google Scholar 

  29. Silvestro L, Tarcomnicu I, Dulea C, Attili NRBN, Ciuca V, Peru D, et al. Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Anal Bioanal Chem. 2013;405(25):8295–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cova D, De Angelis L, Giavarini F, Palladini G, Perego R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers-PubMed. Int J Clin Pharmacol Ther Toxicol. 1992;30(1):29–33.

    CAS  PubMed  Google Scholar 

  31. Barreca D, Laganà G, Bruno G, Magazù S, Bellocco E. Diosmin binding to human serum albumin and its preventive action against degradation due to oxidative injuries. Biochimie. 2013;95(11):2042–9.

    Article  CAS  PubMed  Google Scholar 

  32. Poór M, Boda G, Mohos V, Kuzma M, Bálint M, Hetényi C, et al. Pharmacokinetic interaction of diosmetin and silibinin with other drugs: Inhibition of CYP2C9-mediated biotransformation and displacement from serum albumin. Biomed Pharmacother. 2018;1(102):912–21.

    Article  Google Scholar 

  33. Mrkalić E, Jelić R, Stojanović S, Sovrlić M. Interaction between olanzapine and human serum albumin and effect of metal ions, caffeine and flavonoids on the binding: a spectroscopic study. Spectrochim Acta A Mol Biomol Spectrosc. 2021;15:249.

    Google Scholar 

  34. Chen X, Xu L, Guo S, Wang Z, Jiang L, Wang F, et al. Profiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MS n. J Chromatogr B Analyt Technol Biomed Life Sci. 2019;15(1124):58–71.

    Google Scholar 

  35. Androutsopoulos V, Wilsher N, Arroo R, Potter G. Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450. Cancer Lett. 2009;274(1):54–60.

    Article  CAS  PubMed  Google Scholar 

  36. Wang L, Chen Q, Zhu L, Li Q, Zeng X, Lu L, et al. Metabolic disposition of luteolin is mediated by the interplay of UDP-glucuronosyltransferases and catechol-O-methyltransferases in rats. Drug Metab Dispos. 2017;45(3):306–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang S, Li X, Niu Y, Liu Y, Zhu Y, Lu X, et al. Identification and screening of chemical constituents with hepatoprotective effects from three traditional Chinese medicines for treating jaundice. J Sep Sci. 2016;39(19):3690–9.

    Article  CAS  PubMed  Google Scholar 

  38. Zeng X, Shi J, Zhao M, Chen Q, Wang L, Jiang H, et al. Regioselective glucuronidation of diosmetin and chrysoeriol by the interplay of glucuronidation and transport in UGT1A9-Overexpressing hela cells. PLoS One. 2016;11(11):e0166239.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Imam F, Al-Harbi NO, Al-Harbi MM, Ansari MA, Zoheir KMA, Iqbal M, et al. Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice. Pharmacol Res. 2015;1(102):1–11.

    Article  Google Scholar 

  40. Hsu CC, Lin MH, Cheng JT, Wu MC. Antihyperglycaemic action of diosmin, a citrus flavonoid, is induced through endogenous β-endorphin in type I-like diabetic rats. Clin Exp Pharmacol Physiol. 2017;44(5):549–55.

    Article  CAS  PubMed  Google Scholar 

  41. Firdous SM, Hazra S, Gopinath SCB, El-Desouky GE, Aboul-Soud MAM. Antihyperlipidemic potential of diosmin in Swiss Albino mice with high-fat diet induced hyperlipidemia. Saudi J Biol Sci. 2021;28(1):109–15.

    Article  CAS  PubMed  Google Scholar 

  42. Perumal S, Langeshwaran K, Selvaraj J, Ponnulakshmi R, Shyamaladevi B, Balasubramanian MP. Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats. Mol Cell Biochem. 2018;449(1–2):27–37.

    Article  CAS  PubMed  Google Scholar 

  43. Martinez-Zapata MJ, Vernooij RW, Uriona Tuma SM, Stein AT, Moreno RM, Vargas E, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2016;4(4):CD003229.

    PubMed  Google Scholar 

  44. Juteau N, Bakri F, Pomies J, Foulon C, Rigaudy P, Pillion G, et al. The human saphenous vein in pharmacology: effect of a new micronized flavonoidic fraction (Daflon 500 mg) on norepinephrine induced contraction-PubMed. Int Angiol. 1995;14(3 Suppl 1):8–13.

    CAS  PubMed  Google Scholar 

  45. Struckmann J, Nicolaides A. Flavonoids. A review of the pharmacology and therapeutic efficacy of Daflon 500 mg in patients with chronic venous insufficiency and related disorders. Angiology. 1994;45(6):495–504.

    Article  Google Scholar 

  46. Damon M, Flandre O, Michel F, Perdrix L, Labrid C, Crastes de Paulet A. Effect of chronic treatment with a purified flavonoid fraction on inflammatory granuloma in the rat. Study of prostaglandin E2 and F2 alpha and thromboxane B2 release and histological changes-PubMed. Arzneimittelforschung. 1987;37(10):1149–53.

    CAS  PubMed  Google Scholar 

  47. Labrid C. Pharmacologic properties of Daflon 500 mg—PubMed. Angiology. 1994;45(6 Pt 2):524–30.

    CAS  PubMed  Google Scholar 

  48. Guilhou JJ, Dereure O, Marzin L, Ouvry P, Zuccarelli F, Debure C, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 1997;48(1):77–85.

    Article  CAS  PubMed  Google Scholar 

  49. Senthamizhselvan O, Manivannan J, Silambarasan T, Raja B. Diosmin pretreatment improves cardiac function and suppresses oxidative stress in rat heart after ischemia/reperfusion. Eur J Pharmacol. 2014;5(736):131–7.

    Article  Google Scholar 

  50. El-Fawal R, El Fayoumi H, Mahmoud H. Effects of diosmin and crocin on metabolic syndrome-associated cardio-vascular complications in rats. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(12):1523–36.

    Article  CAS  PubMed  Google Scholar 

  51. Queenthy S, Prince P, John B. Diosmin prevents isoproterenol-induced heart mitochondrial oxidative stress in rats. Cardiovasc Toxicol. 2018;18(2):120–30.

    Article  Google Scholar 

  52. Queenthy S, Prince P, John B. Diosmin prevents left ventricular hypertrophy, adenosine triphosphatases dysfunction and electrolyte imbalance in experimentally induced myocardial infarcted rats. Eur J Pharmacol. 2017;5(814):124–9.

    Google Scholar 

  53. de Almeida GKM, de Jesus ICG, Mesquita T, Miguel-dos-Santos R, dos Santos PH, de Moraes ER, et al. Post-ischemic reperfusion with diosmin attenuates myocardial injury through a nitric oxidase synthase-dependent mechanism. Life Sci. 2020;258:118188.

    Article  PubMed  Google Scholar 

  54. Friesenecker B, Tsai AG, Allegra C, Intaglietta M. Oral administration of purified micronized flavonoid fraction suppresses leukocyte adhesion in ischemia-reperfusion injury: In vivo observations in the hamster skin fold. Int J Microcirc Exp. 1994;14(1–2):50–5.

    Article  CAS  Google Scholar 

  55. Sirlak M, Akar A, Eryilmaz S, Cetinkanat E, Ozcinar E, Kaya B, et al. Micronized purified flavonoid fraction in pretreating CABG patients—PubMed. Texas Hear Inst J. 2010;37(2):172–7.

    Google Scholar 

  56. Struckmann J. Pharmacological and pharmacoclinical properties of Dalfon 500 mg®. Drugs of Today. 1995;31(SUPPL. E):29–36.

    CAS  Google Scholar 

  57. Dholakiya SL, Benzeroual KE. Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-α expression. Toxicol Vitr. 2011;25(5):1039–44.

    Article  CAS  Google Scholar 

  58. Berköz M. Diosmin suppresses the proinflammatory mediators in lipopolysaccharide-induced RAW264.7 macrophages via NF-κB and MAPKs signal pathways. Gen Physiol Biophys. 2019;38(4):315–24.

    Article  PubMed  Google Scholar 

  59. Zaragozá C, Villaescusa L, Monserrat J, Zaragozá F, Álvarez-Mon M. Potential therapeutic anti-inflammatory and immunomodulatory effects of dihydroflavones, flavones, and flavonols. Molecules. 2020;25(4):1017.

    Article  PubMed Central  Google Scholar 

  60. Zheng Y, Zhang R, Shi W, Li L, Liu H, Chen Z, et al. Metabolism and pharmacological activities of the natural health-benefiting compound diosmin. Food Funct. 2020;11(10):8472–92.

    Article  CAS  PubMed  Google Scholar 

  61. Crespo ME, Gálvez J, Cruz T, Ocete MA, Zarzuelo A. Anti-inflammatory activity of diosmin and hesperidin in rat colitis induced by TNBS. Planta Med. 1999;65(7):651–3.

    Article  CAS  PubMed  Google Scholar 

  62. Devaki T, Binuclara J, Raghunandakumar S, Asokkumar S, Naveenkumar C, Premkumar T. Anti-fibrotic effect of diosmin against DMN-induced liver fibrosis in rats: a biochemical analysis. Int J Res Pharm Nano Sci. 2013;2(3):283–92.

    Google Scholar 

  63. Queenthy S, John B. Diosmin exhibits anti-hyperlipidemic effects in isoproterenol induced myocardial infarcted rats. Eur J Pharmacol. 2013;718(1–3):213–8.

    Article  CAS  PubMed  Google Scholar 

  64. Mirzaee S, Mansouri E, Shirani M, Zeinvand-Lorestani M, Khodayar MJ. Diosmin ameliorative effects on oxidative stress and fibrosis in paraquat-induced lung injury in mice. Environ Sci Pollut Res. 2019;26(36):36468–77.

    Article  CAS  Google Scholar 

  65. Eraslan G, Sarıca ZS, Bayram LÇ, Tekeli MY, Kanbur M, Karabacak M. The effects of diosmin on aflatoxin-induced liver and kidney damage. Environ Sci Pollut Res. 2017;24:27931–41.

    Article  CAS  Google Scholar 

  66. EL-Dakhly SM, Salama AAA, Hassanin SOM, Yassen NN, Hamza AA, Amin A. Aescin and diosmin each alone or in low dose-combination ameliorate liver damage induced by carbon tetrachloride in rats. BMC Res Notes. 2020;13:259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Elhelaly AE, AlBasher G, Alfarraj S, Almeer R, Bahbah EI, Fouda MMA, et al. Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats. Environ Sci Pollut Res. 2019;26(34):35151–62.

    Article  CAS  Google Scholar 

  68. Lamidi IY, Mikail HG, Adamu S, Akefe IO, Tijjani MB, Salihu SI, et al. Flavonoid fractions of diosmin and hesperidin mitigate lead acetate-induced biochemical, oxidative stress, and histopathological alterations in Wistar rats. Toxicol Res. 2021;1:1–12.

    Google Scholar 

  69. Ali N, AlAsmari AF, Imam F, Ahmed MZ, Alqahtani F, Alharbi M, et al. Protective effect of diosmin against doxorubicin-induced nephrotoxicity. Saudi J Biol Sci. 2021;28(8):4375–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Peruru R, Dodoala S. Therapeutic potential of diosmin, a citrus flavonoid against arsenic-induced neurotoxicity via suppression of NOX 4 and its subunits. Indian J Pharmacol. 2021;53(2):132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tekeli MY, Eraslan G, Çakır Bayram L, Soyer SZ. Effect of diosmin on lipid peoxidation and organ damage against subacute deltamethrin exposure in rats. Environ Sci Pollut Res. 2020;28(13):15890–908.

    Article  Google Scholar 

  72. Abogresha NM, Mohammed SS, Hosny MM, Abdallah HY, Gadallah AM, Greish SM. Diosmin mitigates cyclophosphamide induced premature ovarian insufficiency in rat model. Int J Mol Sci. 2021;22(6):3044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Germoush MO. Diosmin protects against cyclophosphamide-induced liver injury through attenuation of oxidative stress, inflammation and apoptosis. Int J Pharmacol. 2016;12(6):644–54.

    Article  CAS  Google Scholar 

  74. Manuel y Keenoy B, Vertommen J, De Leeuw I. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients—PubMed. Diabetes Nutr Metab. 1999;12(4):256–63.

    CAS  PubMed  Google Scholar 

  75. Pari L, Srinivasan S. Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. Biomed Pharmacother. 2010;64(7):477–81.

    Article  CAS  PubMed  Google Scholar 

  76. Pari L, Srinivasan S, Saddiq M. Preventive effect of diosmin, a bioflavonoid, on glycoprotein changes in streptozotocin-nicotinamide-induced type 2 diabetic rats. Int J Pharm Sci Res. 2010;1(10):89–95.

    Google Scholar 

  77. Srinivasan S, Pari L. Antihyperlipidemic effect of diosmin: a citrus flavonoid on lipid metabolism in experimental diabetic rats. J Funct Foods. 2013;5(1):484–92.

    Article  CAS  Google Scholar 

  78. Kampmann U, Christensen B, Nielsen TS, Pedersen SB, Ørskov L, Lund S, et al. GLUT4 and UBC9 protein expression is reduced in muscle from type 2 diabetic patients with severe insulin resistance. PLoS One. 2011;6(11):e27854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ali FEM, Bakr AG, Abo-youssef AM, Azouz AA, Hemeida RAM. Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis. Life Sci. 2018;15(207):50–60.

    Article  Google Scholar 

  80. Ali FEM, Azouz AA, Bakr AG, Abo-youssef AM, Hemeida RAM. Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: the role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway. Food Chem Toxicol. 2018;1(120):294–304.

    Article  Google Scholar 

  81. Lewinska A, Adamczyk-Grochala J, Kwasniewicz E, Deregowska A, Wnuk M. Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity. Toxicol Lett. 2017;4(265):117–30.

    Article  Google Scholar 

  82. Lewinska A, Siwak J, Rzeszutek I, Wnuk M. Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line. Toxicol Vitr. 2015;29(3):417–25.

    Article  CAS  Google Scholar 

  83. Dung TD, Lin CH, Binh TV, Hsu HH, Su CC, Lin YM, et al. Diosmin induces cell apoptosis through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells and blocks tumour growth in xenografted nude mice. Food Chem. 2012;132(4):2065–73.

    Article  CAS  Google Scholar 

  84. Álvarez N, Vicente V, Martínez C. Synergistic effect of diosmin and interferon-α on metastatic pulmonary melanoma. Cancer Biother Radiopharm. 2009;24(3):347–52.

    PubMed  Google Scholar 

  85. Zhao Y, Zhang J, Liu W. Diosmin regulates oxidative stress and inflammatory marker levels in N-Methyl-N-nitrosourea-induced gastric carcinogenesis in rats. J Environ Pathol Toxicol Oncol. 2020;39(4):375–84.

    Article  PubMed  Google Scholar 

  86. Bertozzi MM, Rossaneis AC, Fattori V, Longhi-Balbinot DT, Freitas A, Cunha FQ, et al. Diosmin reduces chronic constriction injury-induced neuropathic pain in mice. Chem Biol Interact. 2017;1(273):180–9.

    Article  Google Scholar 

  87. Carballo-Villalobos AI, González-Trujano ME, Pellicer F, Alvarado-Vásquez N, López-Muñoz FJ. Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats. Biomed Pharmacother. 2018;1(97):310–20.

    Article  Google Scholar 

  88. Carballo-Villalobos AI, González-Trujano ME, Pellicer F, López-Muñoz FJ. Antihyperalgesic effect of hesperidin improves with diosmin in experimental neuropathic pain. Biomed Res Int. 2016;2016:8263463.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Adamante G, de Almeida AS, Rigo FK, da Silva SE, Coelho YO, De Prá SDT, et al. Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice. Life Sci. 2019;1(216):215–26.

    Article  Google Scholar 

  90. Sarhan HKA, Saleh AMA, Hammam OAE, Atta AH, El-Nehrery IM. The protective role of Diosmin, Hesperidine combination against heavy metals toxicity in Wistar albino rats: BIOCHEMICAL, IMMUNOHISTOCHEMICAL AND MOLECULAR STUDIEs. Egypt J Chem. 2021;64(8):4531–43.

    Article  Google Scholar 

  91. Quintieri L, Palatini P, Nassi A, Ruzza P, Floreani M. Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes. Biochem Pharmacol. 2008;75(6):1426–37.

    Article  CAS  PubMed  Google Scholar 

  92. Quintieri L, Bortolozzo S, Stragliotto S, Moro S, Pavanetto M, Nassi A, et al. Flavonoids diosmetin and hesperetin are potent inhibitors of cytochrome P450 2C9-mediated drug metabolism in vitro. Drug Metab Pharmacokinet. 2010;25(5):466–76.

    Article  CAS  PubMed  Google Scholar 

  93. Quintieri L, Palatini P, Moro S, Floreani M. Inhibition of cytochrome P450 2C8-mediated drug metabolism by the flavonoid diosmetin. Drug Metab Pharmacokinet. 2011;26(6):559–68.

    Article  CAS  PubMed  Google Scholar 

  94. Chen JJ, Zhang JX, Zhang XQ, Qi MJ, Shi MZ, Yang J, et al. Effects of diosmetin on nine cytochrome P450 isoforms, UGTs and three drug transporters in vitro. Toxicol Appl Pharmacol. 2017;1(334):1–7.

    Article  CAS  Google Scholar 

  95. Bedada SK, Neerati P. Modulation of CYP3A enzyme activity by diosmin and its consequence on carbamazepine pharmacokinetics in rats. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(2):115–21.

    Article  CAS  PubMed  Google Scholar 

  96. Rajnarayana K, Reddy MS, Krishna DR. Diosmin pretreatment affects bioavailability of metronidazole. Eur J Clin Pharmacol. 2003;58(12):803–7.

    Article  CAS  PubMed  Google Scholar 

  97. Rajnarayana K, Venkatesham A, Krishna DR. Bioavailability of diclofenac sodium after pretreatment with diosmin in healthy volunteers. Drug Metabol Drug Interact. 2007;22(2–3):165–74.

    CAS  PubMed  Google Scholar 

  98. Rajnarayana K, Venkatesham A, Nagulu M, Srinivas M, Krishna DR. Influence of diosmin pretreatment on the pharmacokinetics of chlorzoxazone in healthy male volunteers. Drug Metabol Drug Interact. 2008;23(3–4):311–22.

    CAS  PubMed  Google Scholar 

  99. Bedada S, Boga P. Influence of diosmin on the metabolism and disposition of carbamazepine in healthy subjects. Xenobiotica. 2017;47(10):879–84.

    Article  CAS  PubMed  Google Scholar 

  100. Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005;77:1–16.

    Article  CAS  PubMed  Google Scholar 

  101. Rettie AE, Jones JP. Clinical and toxicological relevance of CYP2C9: Drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol. 2005;45:477–94.

    Article  CAS  PubMed  Google Scholar 

  102. Yacobi A, Zlotnick S, Colaizzi J, Moros D, Masson E, Abolfathi Z, et al. A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine. Clin Pharmacol Ther. 1999;65(4):389–94.

    Article  CAS  PubMed  Google Scholar 

  103. Hye HY, Lee M, Hye JC, Sang KL, Kim DH. Effects of diosmin, a flavonoid glycoside in citrus fruits, on P-glycoprotein-mediated drug efflux in human intestinal caco-2 cells. J Agric Food Chem. 2007;55(18):7620–5.

    Article  Google Scholar 

  104. Neerati P, Bedada S. Effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine in rats. Pharmacol Rep. 2015;67(2):339–44.

    Article  CAS  PubMed  Google Scholar 

  105. Bedada SK, Boga PK, Kotakonda HK. The effect of diosmin on the pharmacokinetics of fexofenadine in healthy human volunteers. Xenobiotica. 2017;47(3):230–5.

    Article  CAS  PubMed  Google Scholar 

  106. Gopalakrishnan V, Iyyam Pillai S, Subramanian SP. Synthesis, spectral characterization, and biochemical evaluation of antidiabetic properties of a new zinc-diosmin complex studied in high fat diet fed-low dose streptozotocin induced experimental type 2 diabetes in rats. Biochem Res Int. 2015;2015:350829.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J basic Clin Pharm. 2016;7(2):27.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Anwer MK, Shakeel F. Measurement and correlation of solubility of diosmin in four pure solvents and β-cyclodextrin solution at 298.15 K to 333.15 K. Chin J Chem Eng. 2015;23(5):812–5.

    Article  CAS  Google Scholar 

  109. Piponski M, Stoimenova TB, Topkoska M, Stefov S, Piponska M, Serafimovska GT. Development and validation of a fast and simple RP-HPLC method for the determination of diosmin and hesperidin. Maced J Chem Chem Eng. 2018;37(2):127–34.

    Article  CAS  Google Scholar 

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Correspondence to Ebtehal El-Demerdash.

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Gerges, S.H., Wahdan, S.A., Elsherbiny, D.A. et al. Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review. Eur J Drug Metab Pharmacokinet 47, 1–18 (2022). https://doi.org/10.1007/s13318-021-00731-y

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