Diosmetin

• Anti-inflammatory
• Antioxidant
• Anticancer
• Vascular protection

• Hepatoprotective
• Neuroprotective
• Antimicrobial
• Antidiabetic
• Antiobesity

Diosmetin (5,7,3′-trihydroxy-4′-methoxyflavone) exerts its diverse biological effects through multiple molecular pathways. As a flavone with three hydroxyl groups and one methoxy group, diosmetin possesses both antioxidant properties and unique pharmacological activities related to its specific structure. Diosmetin is the aglycone form of diosmin, a flavonoid glycoside commonly used for vascular conditions. In the body, diosmin is metabolized to diosmetin by intestinal microflora, making diosmetin the bioactive form responsible for many of diosmin’s therapeutic effects.

As an antioxidant, diosmetin scavenges reactive oxygen species (ROS) and free radicals through its hydroxyl groups, which can donate hydrogen atoms to neutralize these harmful molecules. The 5,7-dihydroxy arrangement in the A-ring and the 3′-hydroxyl in the B-ring contribute significantly to its radical scavenging capacity. Beyond direct antioxidant effects, diosmetin activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1). As an anti-inflammatory agent, diosmetin inhibits the nuclear factor-kappa B (NF-κB) signaling pathway by preventing IκB kinase (IKK) activation and subsequent nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory genes.

It suppresses the production of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Diosmetin also modulates the mitogen-activated protein kinase (MAPK) pathway, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties. In the vascular system, diosmetin demonstrates protective effects through several mechanisms. It improves venous tone and lymphatic drainage by increasing norepinephrine-induced contraction of veins and reducing capillary hyperpermeability.

This mechanism explains its benefits for chronic venous insufficiency and hemorrhoids. Diosmetin also protects endothelial cells by reducing oxidative stress and inflammation, enhancing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS), and inhibiting platelet aggregation. In cancer cells, diosmetin demonstrates multiple anticancer mechanisms. It induces apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways by modulating the expression of Bcl-2 family proteins, activating caspases, and promoting cytochrome c release.

Diosmetin inhibits cancer cell proliferation by arresting the cell cycle at G1 or G2/M phases through regulation of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as p21 and p27. It also suppresses cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). Additionally, diosmetin has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling. A particularly significant anticancer mechanism of diosmetin is its ability to inhibit drug efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

This inhibition can enhance the intracellular accumulation and efficacy of chemotherapeutic agents, potentially overcoming multidrug resistance in cancer cells. In the liver, diosmetin exhibits hepatoprotective effects by reducing oxidative stress, inflammation, and lipid accumulation. It activates AMP-activated protein kinase (AMPK), which enhances fatty acid oxidation and reduces lipogenesis, potentially benefiting conditions like non-alcoholic fatty liver disease (NAFLD). Diosmetin also induces phase II detoxification enzymes through Nrf2 activation, enhancing the liver’s capacity to metabolize and eliminate toxins.

In metabolic regulation, diosmetin improves insulin sensitivity and glucose metabolism by activating AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ). It also inhibits adipogenesis and lipid accumulation in adipocytes, contributing to its potential anti-obesity effects. Recent research has identified diosmetin as a potent inhibitor of several drug-metabolizing enzymes and transporters, including cytochrome P450 enzymes (particularly CYP1A2, CYP2C9, and CYP3A4), organic anion-transporting polypeptides (OATPs), and BCRP. This inhibitory activity is stronger than that of its glycoside form diosmin, suggesting that diosmetin may have a higher potential for drug interactions.

The methoxy group at the 4′-position of diosmetin contributes to its unique pharmacological profile compared to other flavones like luteolin. This structural feature enhances its lipophilicity and membrane permeability while maintaining significant antioxidant and anti-inflammatory activities. The balance of hydroxyl and methoxy groups in diosmetin results in a compound with moderate bioavailability and diverse biological activities, making it a promising candidate for various therapeutic applications.

Optimal dosage ranges for diosmetin in humans have not been well established through clinical trials. Most clinical research has focused on diosmin, which is metabolized to diosmetin in the body. For diosmin, typical therapeutic doses range from 500-2000 mg daily, which would yield variable amounts of diosmetin depending on individual gut microbiota composition and activity. For isolated diosmetin, which is rarely available as a standalone supplement, estimated effective doses based on preclinical studies and limited human research would range from 50-200 mg daily.

It’s important to note that diosmetin is often found in plant extracts alongside other flavonoids, making precise dosing recommendations challenging.

Diosmetin has moderate oral bioavailability, estimated at approximately 10-20% in animal studies. This is higher than many other flavonoids due to its balanced hydroxyl/methoxy structure, which provides a good compromise between water solubility and lipophilicity. The 4′-methoxy group increases lipophilicity compared to luteolin (its non-methylated counterpart), potentially enhancing passive diffusion across cell membranes. However, diosmetin’s bioavailability is still limited by several factors, including first-pass metabolism in the liver, efflux by P-glycoprotein transporters in the intestine, and phase II metabolism (primarily glucuronidation and sulfation).

Interestingly, diosmetin is also formed in the body through the metabolism of diosmin, a flavonoid glycoside commonly used for vascular conditions. After oral administration, diosmin is poorly absorbed directly and must be hydrolyzed by intestinal microflora to release diosmetin, which is then absorbed and subsequently undergoes extensive metabolism. This complex absorption and metabolism pathway contributes to the variable bioavailability observed in different individuals, which may be influenced by gut microbiota composition.

Nanoemulsion formulations – can increase bioavailability by 3-10 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects diosmetin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexes – enhance lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Co-administration with probiotics – may enhance conversion of diosmin to diosmetin by modulating gut microbiota, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, Solid dispersion techniques – enhance dissolution rate and solubility, Co-administration with other flavonoids that may compete for metabolic enzymes, potentially extending diosmetin’s half-life

Diosmetin is best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other flavonoids may enhance diosmetin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For vascular conditions, consistent daily dosing is important, with some evidence suggesting that divided doses (morning and evening) may maintain more consistent blood levels due to diosmetin’s relatively short half-life (approximately 2-4 hours in animal studies). For anti-inflammatory and antioxidant effects, timing is less critical than consistency of use.

When diosmetin is consumed as a metabolite of diosmin, allowing sufficient time for intestinal microflora to hydrolyze diosmin to diosmetin is important, which suggests taking it at least 30-60 minutes before meals may be beneficial for some individuals, though this may vary based on individual gut microbiota composition. Enhanced delivery formulations like nanoemulsions or liposomes may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. It’s worth noting that diosmetin has been identified as an inhibitor of several drug-metabolizing enzymes and transporters, including cytochrome P450 enzymes and P-glycoprotein. Therefore, spacing diosmetin supplementation at least 2 hours apart from medications may help minimize potential drug interactions.

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Allergic reactions (rare)
• Mild abdominal pain (uncommon)
• Skin rash (rare)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Bleeding disorders (due to potential antiplatelet activity)
• Hormone-sensitive conditions (due to potential phytoestrogenic effects)
• Individuals taking medications metabolized by CYP1A2, CYP2C9, or CYP3A4 (due to potential interactions)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to diosmetin’s potential antiplatelet effects)
• Cytochrome P450 substrates (diosmetin inhibits several CYP enzymes, particularly CYP1A2, CYP2C9, and CYP3A4, potentially affecting the metabolism of drugs that are substrates for these enzymes)
• P-glycoprotein substrates (diosmetin inhibits P-glycoprotein, potentially altering the transport and absorption of drugs that are P-gp substrates)
• Breast cancer resistance protein (BCRP) substrates (diosmetin inhibits BCRP, potentially affecting the disposition of drugs that are BCRP substrates)
• Organic anion-transporting polypeptide (OATP) substrates (diosmetin inhibits OATPs, potentially affecting the hepatic uptake of drugs that are OATP substrates)
• Statins (potential for increased bioavailability and risk of side effects, particularly for those metabolized by CYP3A4 like atorvastatin and simvastatin)
• Calcium channel blockers (potential for increased bioavailability and enhanced effects)
• Benzodiazepines (potential for increased bioavailability and enhanced sedative effects)
• Immunosuppressants (may interfere with therapeutic effects through immunomodulatory actions)
• Antidiabetic medications (may enhance blood glucose-lowering effects)

Due to limited human clinical data on isolated diosmetin, a definitive upper limit has not been established. Based on safety data for diosmin (which is metabolized to diosmetin) and animal toxicity studies with diosmetin, doses up to 200 mg of diosmetin daily appear to be well-tolerated in most individuals. For general supplementation, doses exceeding 200 mg of diosmetin or 1000 mg of standardized extract daily are not recommended without medical supervision due to potential drug interactions and limited long-term safety data at higher doses.

It ‘s important to note that diosmetin has been identified as a more potent inhibitor of drug-metabolizing enzymes and transporters than its glycoside form diosmin, suggesting a higher potential for drug interactions that should be considered

when determining appropriate dosing.

Diosmetin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Plant extracts containing diosmetin, such as citrus extracts or olive leaf extracts, are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of diosmetin specifically.

Diosmin, which is metabolized to diosmetin in the body, is available as a dietary supplement in the United States but is not FDA-approved as a drug, unlike in some European countries.

Eu: In the European Union, diosmetin is not approved as a medicinal product. Plant extracts containing diosmetin may be sold as food supplements, subject to the general food safety regulations. The European Food Safety Authority (EFSA) has not issued specific health claims for diosmetin. However, diosmin (which is metabolized to diosmetin) is approved as a medicinal product in several EU countries for the treatment of chronic venous insufficiency and hemorrhoids. It is available both as a prescription and over-the-counter medication depending on the country.

France: In France, diosmin-containing medications (which lead to diosmetin formation in the body) are widely used and are available both by prescription and over-the-counter. These products are approved for the treatment of venous insufficiency and hemorrhoids. Diosmetin itself is not specifically regulated as a standalone ingredient.

Canada: Health Canada regulates plant extracts containing diosmetin as Natural Health Products (NHPs). Several products containing these extracts have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims related to traditional use. Diosmin-containing products are also available as NHPs for vascular health. Isolated diosmetin is not specifically approved as a standalone ingredient.

Australia: The Therapeutic Goods Administration (TGA) regulates plant extracts containing diosmetin as complementary medicines. Several products containing these extracts are listed on the Australian Register of Therapeutic Goods (ARTG). Traditional use claims are permitted with appropriate evidence of traditional use. Diosmin-containing products are available for vascular health. Diosmetin as an isolated compound is not specifically regulated.

China: Plant sources of diosmetin, such as citrus peels, are recognized in the Chinese Pharmacopoeia as traditional Chinese medicines. Various formulations containing these herbs are approved for specific indications based on traditional use and modern research. Diosmetin as an isolated compound is primarily used in research rather than as an approved therapeutic agent.

Japan: Plant sources of diosmetin are included in various traditional Japanese medicine formulations. Diosmetin as an isolated compound is not specifically regulated for therapeutic use. The Japanese Ministry of Health, Labour and Welfare permits diosmetin as a natural component of food ingredients derived from its plant sources.

Medium to high

Isolated diosmetin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $200-$500 per gram, making

it relatively expensive but more affordable than many other isolated flavonoids. Plant extracts containing diosmetin, such as citrus extracts or olive leaf extracts, typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Diosmin supplements (which are metabolized to diosmetin in the body) typically cost $0.30-$1.50 per day for basic formulations and $1.50-$4.00 per day for premium, micronized formulations. Enhanced delivery formulations such as nanoemulsions or liposomes generally cost $3.00-$8.00 per day.

The cost-effectiveness of diosmetin must be evaluated in the context of the specific health condition and the form in which it is consumed. For vascular conditions such as chronic venous insufficiency or hemorrhoids, diosmin supplements (which are metabolized to diosmetin) offer good value despite their moderate cost, as they have substantial clinical evidence supporting their efficacy for these specific conditions. Micronized diosmin formulations, while more expensive, provide better bioavailability and potentially superior clinical outcomes, justifying their higher cost for these indications. For general antioxidant and anti-inflammatory benefits, plant extracts containing diosmetin along with other complementary flavonoids may offer better value than isolated diosmetin, as they provide a broader spectrum of beneficial compounds at a lower cost.

Citrus extracts and olive leaf extracts are particularly cost-effective sources of diosmetin and related flavonoids. For specific applications like cancer therapy, where diosmetin’s ability to inhibit drug efflux transporters may enhance the efficacy of chemotherapeutic agents, the higher cost of more purified or enhanced delivery formulations may be justified. However, such applications should only be considered under medical supervision as part of a comprehensive treatment plan. When comparing the cost-effectiveness of diosmetin to other supplements with similar indications: For vascular conditions, diosmin/diosmetin is comparable in cost to horse chestnut extract and rutin but may offer superior efficacy based on clinical evidence.

For general antioxidant and anti-inflammatory benefits, diosmetin-containing plant extracts are generally more cost-effective than many specialized antioxidant supplements while providing comparable benefits. For metabolic conditions like diabetes and obesity, diosmetin-containing supplements are moderately priced compared to alternatives, but the clinical evidence is still emerging, making their value proposition less clear. Enhanced delivery systems such as nanoemulsions, liposomes, or SEDDS offer better bioavailability and potentially superior therapeutic outcomes, which may justify their higher cost for specific health conditions or individuals with absorption issues. The cost-effectiveness is also influenced by individual factors such as gut microbiota composition (which affects conversion of diosmin to diosmetin) and specific health conditions, making personalized approaches important for maximizing value.

Pure diosmetin is moderately stable, with a typical shelf life of 2-3 years when properly stored. The methoxy group at the 4′-position provides better stability compared to its non-methylated counterpart luteolin. Standardized herbal extracts containing diosmetin typically have a shelf life of 1-2 years from the date of manufacture. Products containing diosmin (which is metabolized to diosmetin) generally have a shelf life of 2-3 years when stored properly.

Enhanced delivery formulations such as nanoemulsions or liposomes generally have shorter shelf lives of 1-2 years, depending on the specific formulation and preservative system.

Store in a cool, dry place away from direct sunlight in airtight, opaque containers. Refrigeration is recommended for liquid formulations and can extend shelf life of extracts containing diosmetin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure diosmetin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

The addition of antioxidants such as vitamin E or ascorbic acid to formulations can help prevent oxidation and extend shelf life. Enhanced delivery formulations may have specific storage requirements provided by the manufacturer, which should be followed carefully to maintain stability and potency. Avoid repeated freeze-thaw cycles, particularly for liquid formulations, as this can destabilize the product.

Exposure to UV light and sunlight – causes photodegradation, though the methoxy group provides some protection compared to more hydroxylated flavonoids, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly of the hydroxyl groups, pH extremes – diosmetin is most stable at slightly acidic to neutral pH (5-7), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – may occur in improperly processed plant extracts, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with diosmetin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Diosmetin itself was not identified or isolated until the modern era, but it is a constituent of several plants that have been used in traditional medicine systems for centuries. While the specific contribution of diosmetin to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the bioactive compounds in these historically important medicinal materials. Diosmetin is found in citrus fruits, olive leaves, and various herbs, all of which have rich histories in traditional medicine. It is also formed in the body as a metabolite of diosmin, a flavonoid glycoside that has been used medicinally for vascular conditions.

In Mediterranean traditional medicine, olive leaves (Olea europaea) have been used for centuries to treat various conditions, including hypertension, fever, malaria, and diabetes. The ancient Egyptians used olive leaf preparations for mummification and to treat infections. In ancient Greece, Hippocrates recommended olive leaf extracts for various ailments, and they were a symbol of purification. Modern research has identified diosmetin as one of the bioactive compounds in olive leaves contributing to their medicinal properties.

Citrus fruits and their peels, which contain diosmetin, have a long history of use in traditional Chinese medicine (TCM), Ayurvedic medicine, and various folk medicine traditions. In TCM, dried citrus peels (Chen Pi) have been used for over 2,000 years to regulate qi (vital energy), dispel dampness, and resolve phlegm. They were traditionally used to treat digestive disorders, coughs with phlegm, abdominal distension, and nausea. The first documented medicinal use of citrus peels appears in the ancient Chinese pharmacopeia ‘Shennong Bencao Jing’ (Divine Farmer’s Materia Medica), compiled around 200-250 CE.

In European herbal medicine, various herbs containing diosmetin, such as oregano (Origanum vulgare) and germander (Teucrium species), were used for their digestive, antimicrobial, and anti-inflammatory properties. These herbs were commonly included in traditional remedies for respiratory infections, digestive disorders, and inflammatory conditions. Diosmin, which is metabolized to diosmetin in the body, has a more recent medicinal history. It was first isolated in 1925 and has been used clinically for vascular conditions since the 1960s, particularly in Europe.

Diosmin was initially derived from the Citrus genus but is now primarily produced semi-synthetically from hesperidin, another citrus flavonoid. Diosmetin was first isolated and characterized in the mid-20th century as part of the scientific investigation into the active components of these traditional medicinal plants. Its structure was elucidated as 5,7,3′-trihydroxy-4′-methoxyflavone, identifying it as the 4′-methyl ether of luteolin. Modern scientific interest in diosmetin began to grow in the late 20th and early 21st centuries as research revealed its antioxidant, anti-inflammatory, and potential anticancer properties.

Recent studies have particularly focused on diosmetin’s ability to inhibit drug efflux transporters, which has opened new avenues for research into its potential applications in cancer therapy and drug resistance. The relationship between diosmin and diosmetin has also been an important area of research, with studies suggesting that diosmetin may be responsible for many of the therapeutic effects attributed to diosmin supplementation.

No meta-analyses specifically on diosmetin are currently available; most analyses focus on diosmin (which is metabolized to diosmetin) or citrus flavonoids as a group.

Limited ongoing trials specifically investigating diosmetin; most research focuses on diosmin or plant extracts containing diosmetin, Several preclinical studies investigating diosmetin’s potential in cancer therapy, particularly focusing on its ability to inhibit drug efflux transporters and enhance the efficacy of chemotherapeutic agents, Research on novel delivery systems to enhance diosmetin’s bioavailability and targeted delivery, Investigations into diosmetin’s potential for metabolic disorders, including diabetes and obesity, Studies on the combination of diosmetin with conventional therapies for enhanced efficacy in various conditions