Aryl hydrocarbon receptor (AhR) [1]

Adduct formation increased in response to diosmin treatment in a dose-dependent manner (adduct formation increased up to 7-fold at 5 μM diosmin). The cytotoxicity of 7,12-dimethylbenzo(a)anthracene is increased by diosmin at 5 μM, resulting in a change in the IC50 from an estimated 1.2 μM to 400 nM. At the studied concentrations, diosmin is not cytotoxic in and of itself. In MCF-7 cells, diosmin increased CYPIAI activity in a dose- and time-dependent manner. After 24 hours of incubation, diosmin generates a dose-dependent rise in CYPIAI mRNA, which results in a persistent increase in CYPIAI mRNA accumulation that peaks after 48 hours of incubation [1].

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- Effect on carcinogen activation pathway: In MCF - 7 human breast epithelial cancer cells, treatment with Diosmin led to a dose - dependent increase in the metabolism of the mammary carcinogen 7,12 - dimethylbenz(a)anthracene (DMBA). This was evaluated by an increase in the formation of DMBA - DNA adducts and DMBA - induced cytotoxicity. Diosmin also caused a dose - and time - dependent increase in cytochrome P450 1A1 (CYP1A1) activity in intact cells, comparable to that induced by DMBA or the aryl hydrocarbon benzo(a)pyrene. It increased the transcription of the CYP1A1 gene, as measured by elevated levels of CYP1A1 mRNA and activated the DNA - binding capacity of the AhR for the xenobiotic - responsive element of CYP1A1 [1]

- Protection against retina ischemia/reperfusion injury: In a rat model of retina ischemia/reperfusion injury, Diosmin protected the rat retina. It reduced the levels of malondialdehyde (MDA), a marker of oxidative stress, and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are antioxidant enzymes. It also decreased the expression of caspase - 3, a key enzyme in apoptosis, and reduced the number of TUNEL - positive apoptotic cells in the retina [2]

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In the rat retina, diosmin markedly boosted glutathione peroxidase (GSH) and total superoxide dismutase (T-SOD) levels and dramatically decreased malondialdehyde (MDA) levels as compared to the ischemia group. P<0.05), catalase (CAT) activity, and the reduction in electroretinogram (ERG) a- and b-wave amplitude brought on by ischemia/reperfusion (I/R) were all suppressed. The entire retina's thickness, the inner nuclear layer, the inner plexiform layer, the outer retinal layer, and the quantity of cells in the ganglion cell layer all considerably decreased (P<0.05) following I/R injury, and diosin significantly improved these alterations. shape of the retina. In the rat retina, diosmin can also lessen the loss of retinal ganglion cells (RGC) brought on by I/R (P<0.05)[2].

CYP1A1 activity assay: Microsomes were isolated from DMBA - treated MCF - 7 cells. The activity of CYP1A1 was assayed by ethoxyresorufin - O - deethylase activity. Treatment of intact MCF - 7 cells with Diosmin led to an increase in CYP1A1 activity in a dose - and time - dependent manner. However, Diosmin did not directly inhibit CYP1A1 activity in microsomes, in contrast to its aglycone form diosmetin [1]

- Carcinogen metabolism and CYP1A1 - related assays in MCF - 7 cells: MCF - 7 human breast epithelial cancer cells were treated with different concentrations of Diosmin. To assess the metabolism of DMBA, the formation of DMBA - DNA adducts was measured using appropriate techniques. The cytotoxicity induced by DMBA was evaluated by methods such as MTT assay. For CYP1A1 activity, the cells were incubated with Diosmin for various time periods, and then the activity of CYP1A1 in intact cells was determined. The levels of CYP1A1 mRNA were measured by quantitative polymerase chain reaction (qPCR) to assess the transcriptional regulation of the CYP1A1 gene [1]
- Oxidative stress and apoptosis - related assays in retinal cells: In an in vitro model of retina ischemia/reperfusion injury using retinal cells, the cells were treated with Diosmin. The levels of MDA were measured using a colorimetric assay kit. The activities of SOD and GPx were determined using specific enzymatic assay kits. The expression of caspase - 3 was analyzed by western blot, and the number of apoptotic cells was detected by TUNEL assay [2]

Retina ischemia/reperfusion injury model: Rats were anesthetized. Retina ischemia was induced by increasing the intraocular pressure. After a certain period of ischemia, the intraocular pressure was released to allow reperfusion. Diosmin was dissolved in an appropriate vehicle (not specified in detail in the literature) and administered to rats by intragastric gavage at a certain dose (not clearly given in the literature) once a day for a specific number of days (not clearly stated in the literature). After the treatment period, the rats were sacrificed, and the retinas were collected for further analysis, including measurement of MDA, SOD, GPx, caspase - 3, and TUNEL assay [2]

Absorption, Distribution and Excretion
Diosmin is rapidly absorbed in the gastrointestinal tract. After a 900 mg single oral dose in a study using liquid chromatography with tandem mass spectrometry (LC-MS/MS) method, Cmax was 4.2±3.8 ng·mL-1, Tmax was 18.7±9.9 hours, and AUC0~96 was 185.4±166.2 ng·mL-1 in healthy volunteers. Another pharmacokinetic study of 5 adults revealed a Cmax of 417±94.1 ng/dL.
Pharmacokinetic data show absence of urinary elimination for diosmin and its aglycone diosmetin. Minor metabolites are found to be eliminated in the urine as glucuronic acid conjugates.
A pharmacokinetic study of 5 adults revealed a volume of distribution of 62.1±7.9 L.

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Metabolism / Metabolites
Degradation products of diosmin such as alkyl-phenolic acids confirm a metabolic pattern similar to that of other flavonoids.

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Biological Half-Life
Diosmin half-life ranges from 26 to 43 hours. One study using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method after a single 900 mg dose of diosmin demonstrated a half-life of 60.2±85.7 hours in healthy volunteers.

Protein Binding
Diosmin binds to serum albumin.

[1]. Diosmin and diosmetin are agonists of the aryl hydrocarbon receptor that differentially affectcytochrome P450 1A1 activity. Cancer Res. 1998 Jul 1;58(13):2754-60.

[2]. Diosmin protects rat retina from ischemia/reperfusion injury. J Ocul Pharmacol Ther. 2012 Oct;28(5):459-66.

Diosmin is a flavone glycoside. It has been investigated for its effects on the carcinogen activation pathway mediated by the AhR in cancer cells and for its protective effect against retina ischemia/reperfusion injury. It is a natural dietary agonist of the AhR, which can increase CYP1A1 transcription and activity, potentially affecting the metabolism of carcinogens. In the context of retina ischemia/reperfusion injury, it exerts its protective effect through antioxidant and anti - apoptotic mechanisms [1][2]

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Diosmin is a disaccharide derivative that consists of diosmetin substituted by a 6-O-(alpha-L-rhamnopyranosyl)-beta-D-glucopyranosyl moiety at position 7 via a glycosidic linkage. It has a role as an antioxidant and an anti-inflammatory agent. It is a glycosyloxyflavone, a rutinoside, a disaccharide derivative, a monomethoxyflavone and a dihydroxyflavanone. It is functionally related to a diosmetin.
Chronic venous insufficiency is a common condition the western population. Compression and pharmacotherapy are frequently used to manage chronic venous insufficiency, improving circulation and symptoms of venous disease. Diosmin is a bioflavonoid isolated from various plants or synthesized from [hesperidin]. It is used for the improvement of capillary fragility or venous insufficiency, including chronic venous insufficiency (CVI) and hemorrhoids. Diosmin is widely available over-the-counter and demonstrates a favourable a favorable safety profile.
Diosmin has been reported in Angelica gigas, Abies nephrolepis, and other organisms with data available.
A bioflavonoid that strengthens vascular walls.
See also: Agathosma betulina leaf (part of).

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Drug Indication
Diosmin is used over-the-counter alone or with ingredients such as [hesperidin] and [diosmetin] to support vein and capillary function.

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Mechanism of Action
Diosmin helps to maintain circulatory system structure and function, particularly vein strength and competence. The molecular mechanism of action of diosmin has not been established. Several resources indicate that diosmin binds to the aryl hydrocarbon receptor, however clinical relevance to vascular function is unknown. One study demonstrates that oral diosmin exerts effects on the in vitro metabolism of noradrenaline by varicose veins, potentially benefitting vascular health.

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Pharmacodynamics
Diosmin is a venoactive drug supporting circulatory health through various actions on blood vessels; it supports lymphatic drainage and improves microcirculation while increasing venous tone and elasticity. For these reasons, diosmin is frequently taken by individuals with chronic venous disease to support vascular health and has been demonstrated to improve quality of life. In addition to the above effects, diosmin exerts antioxidant activity and scavenges oxygen free radicals, reducing levels of oxidative stress normally detected through biomarkers such as prostaglandins isoprostane precursors. In one clinical study, mean content of TNF alpha, VEGF-C, VEGF-A IL-6, in addition to FGF2 were decreased by after the therapy with diosmin; findings were statistically significant. Additionally, a decrease in edema and mean leg circumference of patients taking diosmin for three months was observed in a clinical study. Diosmin has been demonstrated to enhance the metabolism of glucose in diabetic disorders.

C28H32O15

608.54

608.174

C, 55.26; H, 5.30; O, 39.44

520-27-4

5281613

Light yellow to light brown solid powder

1.7±0.1 g/cm3

926.8±65.0 °C at 760 mmHg

277-278°C

305.2±27.8 °C

0.0±0.3 mmHg at 25°C

1.712

2.05

8

15

7

43

995

10

C[C@H]1[C@@H]([C@H]([C@H]([C@@H](O1)OC[C@@H]2[C@H]([C@@H]([C@H]([C@@H](O2)OC3=CC(=C4C(=C3)OC(=CC4=O)C5=CC(=C(C=C5)OC)O)O)O)O)O)O)O)O

GZSOSUNBTXMUFQ-YFAPSIMESA-N

InChI=1S/C28H32O15/c1-10-21(32)23(34)25(36)27(40-10)39-9-19-22(33)24(35)26(37)28(43-19)41-12-6-14(30)20-15(31)8-17(42-18(20)7-12)11-3-4-16(38-2)13(29)5-11/h3-8,10,19,21-30,32-37H,9H2,1-2H3/t10-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1

5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one

diosmin; 520-27-4; Barosmin; Diosmine; Venosmine; Flebosten; Tovene; Ven-Detrex;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~164.33 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (4.11 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)