Rutin

• Antioxidant protection
• Vascular health
• Anti-inflammatory
• Capillary strengthening

• Blood glucose regulation
• Neuroprotection
• Cardiovascular support
• Venous insufficiency relief
• Edema reduction
• Skin health

Rutin exerts its diverse biological effects through multiple mechanisms at the molecular level. As a potent antioxidant, rutin directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), including superoxide anions, hydroxyl radicals, peroxyl radicals, and peroxynitrite. This free radical scavenging activity is primarily attributed to the hydroxyl groups in its structure, particularly those in the B-ring of the flavonoid moiety. Beyond direct scavenging, rutin enhances the body’s endogenous antioxidant defense system by upregulating the expression and activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1).

This upregulation occurs partly through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of cellular antioxidant responses. Rutin also exhibits metal-chelating properties, binding transition metals like iron and copper that can catalyze oxidative reactions, thereby preventing lipid peroxidation and oxidative damage to cellular components. In the vascular system, rutin strengthens capillaries and improves microcirculation through multiple mechanisms. It inhibits the enzyme hyaluronidase, which degrades hyaluronic acid in the capillary wall, thereby preserving capillary integrity.

Rutin also modulates the expression of vascular endothelial growth factor (VEGF) and its receptors, promoting angiogenesis and vascular repair. Additionally, it enhances nitric oxide (NO) production by activating endothelial nitric oxide synthase (eNOS), leading to vasodilation and improved blood flow. The anti-inflammatory effects of rutin stem from its ability to inhibit key inflammatory signaling pathways. It suppresses the activation of nuclear factor-kappa B (NF-κB), a transcription factor that regulates the expression of numerous pro-inflammatory genes.

Rutin also inhibits the mitogen-activated protein kinase (MAPK) pathway, including p38 MAPK, JNK, and ERK, which are involved in inflammatory responses. These actions result in decreased production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Furthermore, rutin inhibits the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), reducing the production of prostaglandins and excessive nitric oxide associated with inflammation. In glucose metabolism, rutin influences several pathways that contribute to its anti-diabetic effects.

It inhibits alpha-glucosidase and alpha-amylase, enzymes involved in carbohydrate digestion, thereby slowing glucose absorption. Rutin enhances insulin sensitivity by activating the insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which promotes glucose uptake in peripheral tissues. It also protects pancreatic beta cells from oxidative stress-induced damage and stimulates insulin secretion. The neuroprotective properties of rutin involve multiple mechanisms, including reduction of oxidative stress in neural tissues, inhibition of acetylcholinesterase (AChE) activity, modulation of neurotransmitter systems, and regulation of neuroinflammatory responses.

Rutin crosses the blood-brain barrier, albeit in limited amounts, and can influence brain function directly. It also promotes the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), supporting neuronal survival and plasticity. In cancer prevention and treatment, rutin demonstrates antiproliferative and pro-apoptotic effects on various cancer cell lines. It induces cell cycle arrest by modulating the expression of cyclins and cyclin-dependent kinases (CDKs).

Rutin triggers apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways, involving activation of caspases and regulation of Bcl-2 family proteins. It also inhibits angiogenesis and metastasis by suppressing matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression. Additionally, rutin exhibits epigenetic effects by inhibiting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), potentially reversing aberrant epigenetic modifications associated with various diseases.

The typical therapeutic dosage of rutin ranges from 500 mg to 1,500 mg per day, with most clinical studies using 500-1,000 mg daily. For general health maintenance and antioxidant support, lower doses of 250-500 mg daily may be sufficient. Higher doses are typically used for specific therapeutic purposes.

General Timing: Rutin is typically taken with meals to enhance absorption and reduce potential gastrointestinal side effects. For twice-daily dosing, morning and evening administration with food is recommended.

Specific Considerations: For conditions involving edema, taking the last dose no later than early evening may help prevent nighttime fluid retention. For allergic conditions, consistent daily timing helps maintain stable blood levels.

Tablets Capsules: Most common form, typically available in 250 mg, 500 mg, and occasionally 1,000 mg strengths.

Powder: Allows for flexible dosing but has a bitter taste. Typically mixed with juice or smoothies to mask flavor.

Combination Products: Often combined with vitamin C, other flavonoids (diosmin, hesperidin), or plant extracts. Dosages vary by formulation.

For those new to rutin supplementation, starting with a lower dose (250-500 mg daily) for the first week and gradually increasing to the target therapeutic dose can help minimize potential digestive discomfort.

Rutin has relatively poor oral bioavailability (approximately 4-7%) due to its low water solubility, limited intestinal absorption, and extensive first-pass metabolism. The large molecular size and glycosidic structure contribute to its limited absorption in the small intestine.

Intestinal Metabolism: In the intestine, rutin is partially hydrolyzed by intestinal microflora to its aglycone form, quercetin, through the cleavage of the glycosidic bond. This bacterial metabolism is a crucial step for rutin absorption, as quercetin is more readily absorbed than the parent compound.

Hepatic Metabolism: After absorption, rutin and its metabolites undergo extensive hepatic metabolism, primarily through phase II conjugation reactions including glucuronidation, sulfation, and methylation. The main metabolites include quercetin glucuronides, quercetin sulfates, and methylated derivatives.

Primary Metabolites: Quercetin-3-O-glucuronide, Quercetin-3′-O-sulfate, Isorhamnetin (3′-O-methylquercetin), Tamarixetin (4′-O-methylquercetin), Various mixed conjugates (glucuronide-sulfates)

Peak Plasma Time: For standard rutin, peak plasma concentrations of metabolites occur approximately 6-8 hours after oral administration, reflecting the time required for intestinal bacterial metabolism and absorption.

Half Life: The elimination half-life of rutin metabolites ranges from 11-28 hours, with considerable individual variation. This relatively long half-life allows for once or twice daily dosing.

Protein Binding: Approximately 75-85% of circulating rutin metabolites are bound to plasma proteins, primarily albumin.

For optimal absorption, rutin should be taken with meals, preferably those containing some fat content. Dividing the daily dose into two administrations (morning and evening with meals) may help maintain more consistent blood levels of active metabolites. Consistency in timing from day to day helps maintain stable therapeutic effects.

Rutin has a favorable safety profile with minimal reported adverse effects in clinical studies. It has been used therapeutically for several decades with a good safety record. Clinical trials have demonstrated safety at doses up to 1,500 mg daily for extended periods. As a naturally occurring flavonoid present in many foods, rutin is generally recognized as safe for most individuals when used appropriately.

• Known hypersensitivity to rutin or other flavonoids
• Bleeding disorders (use with caution due to potential antiplatelet effects)
• Scheduled surgery (discontinue at least 2 weeks before due to potential anticoagulant effects)
• Pregnancy and lactation (insufficient safety data, use only if clearly needed and under medical supervision)
• Severe liver or kidney disease (use with caution due to limited elimination data)

Pregnancy: Category C – Animal reproduction studies have not demonstrated fetal risk, but there are no adequate well-controlled studies in pregnant women. Use only if potential benefit justifies potential risk to the fetus.

Lactation: Limited data available. Small amounts may be excreted in breast milk. Use caution and consider risk-benefit ratio.

Pediatric: Safety and efficacy not established in children. Limited clinical data available for pediatric use.

Geriatric: No specific dose adjustments required, but start at lower doses and monitor for side effects due to potential decreased renal/hepatic function and increased likelihood of drug interactions.

Renal Impairment: Use with caution in moderate to severe renal impairment. Consider reduced dosing.

Hepatic Impairment: Use with caution in moderate to severe hepatic impairment. Consider reduced dosing.

Acute Toxicity: Rutin has very low acute toxicity. Animal studies show LD50 values greater than 5,000 mg/kg body weight, indicating a wide margin of safety.

Chronic Toxicity: Long-term studies have not identified significant toxicity concerns at therapeutic doses. No evidence of organ toxicity in studies up to 6 months duration at doses up to 1,500 mg/day.

Genotoxicity: No evidence of mutagenic or genotoxic effects in standard assays.

Carcinogenicity: No evidence of carcinogenic potential in available studies.

No official upper limit has been established. Clinical studies have used doses up to 1,500 mg daily without significant adverse effects. Doses above 2,000 mg daily have not been well studied and are not recommended without medical supervision due to potential for increased risk of side effects and drug interactions.

Classification: Dietary Supplement

Approval Status: Not approved as a drug in the United States. Marketed as a dietary supplement under DSHEA (Dietary Supplement Health and Education Act) regulations.

Permitted Claims: Structure/function claims related to vascular health, antioxidant support, and circulation are permitted with appropriate disclaimer. Disease claims (such as treating chronic venous insufficiency or hemorrhoids) are not allowed without drug approval.

Restrictions: Must comply with dietary supplement GMP (Good Manufacturing Practices) regulations. Cannot be marketed with claims to treat, cure, or prevent specific diseases.

Harmonization Efforts: Ongoing efforts to harmonize regulatory approaches to botanical products including rutin across different regions, particularly within the EU.

Evidence Requirements: Increasing emphasis on clinical evidence to support health claims, with regulatory bodies requiring more robust scientific substantiation.

Safety Monitoring: Enhanced post-market surveillance systems for dietary supplements and botanical medicines in many jurisdictions.

United States: Must include standard supplement facts panel, appropriate structure/function claim disclaimers, and cannot make disease claims.

European Union: Medicinal products must include approved indications, dosage information, and safety warnings. Food supplements must comply with food labeling regulations and health claim restrictions.

General Requirements: Most jurisdictions require batch/lot numbers, expiration dates, storage conditions, and manufacturer information.

European Union: Rutin is not considered a novel food in the EU as it has a history of consumption before May 15, 1997.

United Kingdom: Not classified as a novel food due to history of use.

Australia New Zealand: Not considered a novel food under FSANZ regulations.

Enhanced Bioavailability Formulations: Novel delivery systems for rutin (liposomal, nanoparticle, etc.) may face additional regulatory scrutiny as they could alter the absorption, distribution, metabolism, and excretion profiles.

Combination Products: Products combining rutin with other bioactives may face more complex regulatory pathways, particularly if synergistic effects are claimed.

Personalized Nutrition: Emerging regulatory frameworks for personalized nutrition may impact how rutin supplements are recommended and marketed based on individual genetic or metabolic profiles.

2024-07-10

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Rutin supplements vary in cost depending on formulation, purity, and brand. Standard rutin supplements are moderately priced compared to other specialty supplements. Enhanced bioavailability formulations and pharmaceutical-grade products typically command higher prices.

Standard Rutin: $15-30 USD for 500-1000 mg daily dose, $0.50-1.00 USD per day for standard formulations, Basic rutin supplements are relatively affordable and widely available. Quality can vary significantly in this price range.

Enhanced Bioavailability Formulations: $30-60 USD for 500-1000 mg daily dose, $1.00-2.00 USD per day, Liposomal, phytosomal, or micronized formulations command premium prices but may offer improved absorption and efficacy.

Pharmaceutical Grade: $40-80 USD for rutin derivatives (e.g., O-(β-hydroxyethyl)-rutosides), $1.30-2.70 USD per day, Pharmaceutical-grade products, particularly semi-synthetic derivatives, are typically more expensive but have stronger clinical evidence supporting their efficacy.

Combination Products: $25-50 USD for products combining rutin with other flavonoids or antioxidants, $0.80-1.70 USD per day, Products combining rutin with complementary compounds like diosmin, hesperidin, or vitamin C may offer better value through synergistic effects.

Regional Variations: Prices vary significantly by country. In European countries where rutin derivatives are prescribed as medications, costs may be partially covered by health insurance. Generic versions are typically 30-50% less expensive than branded products.

Vs Other Supplements: Rutin is moderately priced compared to other specialty supplements. It is typically more expensive than basic supplements like vitamin C or B vitamins, comparable to mid-range supplements like CoQ10 or alpha-lipoic acid, and less expensive than premium supplements like NMN or resveratrol.

Vs Pharmaceuticals: For vascular conditions like chronic venous insufficiency, rutin supplements are generally less expensive than prescription medications such as pentoxifylline or surgical interventions, making them a cost-effective first-line or adjunctive therapy.

Formulation Selection: For most conditions, standard rutin supplements provide reasonable value. Enhanced bioavailability formulations may be worth the additional cost for individuals with absorption issues or those who haven’t responded adequately to standard formulations.

Dosing Strategies: For chronic conditions, using the recommended therapeutic dose during initial treatment (typically 1000 mg daily for 2-3 months), then reducing to a maintenance dose (500 mg daily) may optimize cost-effectiveness.

Purchasing Tips: Bulk purchases may reduce per-dose cost, Subscription services often offer 10-20% discounts, Look for sales or promotional discounts from reputable suppliers, Consider combination products if you would otherwise purchase multiple supplements separately

When evaluating cost-efficiency, consider the potential long-term savings from preventing progression of vascular disease, which can lead to costly complications such as venous ulcers, deep vein thrombosis, or surgical interventions. These indirect savings may significantly outweigh the direct costs of rutin supplementation.

Standard rutin supplements typically have a shelf life of 2-3 years when stored properly. The actual stability can vary based on formulation, packaging, and storage conditions.

Temperature: Store at room temperature (15-25°C or 59-77°F). Avoid exposure to temperatures above 30°C (86°F), as higher temperatures can accelerate degradation through oxidation and hydrolysis reactions.

Humidity: Keep in a dry place with relative humidity below 60%. Rutin can absorb moisture, which may lead to hydrolysis of the glycosidic bond and degradation.

Light: Protect from direct light, especially sunlight and UV radiation, which can cause photodegradation. Rutin is particularly susceptible to photodegradation due to its flavonoid structure.

Container: Keep in the original container, preferably in opaque or amber bottles with tight-fitting lids. Blister packs provide good protection against moisture and light.

Special Considerations: Some formulations may include stabilizers such as vitamin C or vitamin E to extend shelf life by protecting against oxidation.

Tablets: Generally stable with shelf life of 2-3 years. Film-coated tablets offer better protection against moisture and oxidation. Inclusion of antioxidants like vitamin C or vitamin E can enhance stability.

Capsules: Moderately stable with shelf life of 2-3 years. Vegetable capsules may be more susceptible to moisture than gelatin capsules. Oxygen absorbers in packaging can improve stability.

Powders: Less stable than solid dosage forms, with shelf life typically 1-2 years due to increased surface area exposed to environmental factors. Should be stored with desiccants.

Liquid Extracts: Least stable form with shelf life of 6-12 months. Often contain preservatives and antioxidants to extend stability. Glycerin-based extracts tend to be more stable than alcohol-based ones.

Synthesis Methods

Natural Sources

Quality Considerations

Sustainability

Market Trends

Ancient Medicine: While rutin itself was not identified until the 20th century, plants rich in rutin have been used in traditional medicine systems for centuries. Buckwheat, one of the richest sources of rutin, has been used in traditional Chinese medicine and European folk medicine for circulatory conditions and to strengthen blood vessels.

Folk Remedies: Rue (Ruta graveolens), from which rutin derives its name, has a long history of use in European folk medicine for various conditions, including eye problems, muscle spasms, and as a ‘blood purifier.’ Many of these traditional applications align with modern understanding of rutin’s vascular and anti-inflammatory properties.

Initial Discovery: Rutin was first isolated in 1842 by August Weiss from the plant Ruta graveolens (common rue). It was initially named ‘rutinic acid’ before being renamed to rutin.

Structural Elucidation: The complete chemical structure of rutin was not fully elucidated until the 1940s, when advances in analytical chemistry allowed for more detailed structural analysis of flavonoid compounds.

Vitamin P Designation: In the 1930s and 1940s, rutin and related flavonoids were briefly classified as ‘Vitamin P’ due to their effects on capillary permeability. This classification was later abandoned as they did not meet the strict definition of vitamins as essential nutrients.

Early Research: Scientific interest in rutin began to grow in the 1940s, with early research focusing on its effects on capillary fragility and permeability. During World War II, there was particular interest in rutin for treating conditions related to capillary fragility.

1950s-1960s: Clinical use expanded with the development of more standardized preparations. Research during this period established rutin’s efficacy for various vascular conditions, particularly those involving capillary fragility.

1970s-1980s: Development of semi-synthetic derivatives of rutin, such as O-(β-hydroxyethyl)-rutosides (HR), which showed improved bioavailability and efficacy for venous conditions. These derivatives became widely used in Europe for chronic venous insufficiency.

1990s-2000s: Increased research into the molecular mechanisms of rutin’s actions, particularly its antioxidant and anti-inflammatory effects. This period saw growing interest in rutin’s potential applications beyond vascular health.

2010s-Present: Expanding research into rutin’s potential applications for metabolic disorders, neurodegenerative conditions, and cancer prevention. Increased focus on improving bioavailability and developing novel delivery systems.

Early Products: The first commercial rutin preparations became available in the 1940s and 1950s, primarily marketed for vascular health and capillary fragility.

Pharmaceutical Formulations: In Europe, particularly Germany, France, and Italy, rutin and its derivatives have been developed as prescription medications for chronic venous insufficiency and related conditions.

Dietary Supplements: In the United States and many other countries, rutin has primarily been marketed as a dietary supplement rather than a pharmaceutical, particularly since the passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994.

Combination Products: Development of combination products containing rutin along with other flavonoids (particularly diosmin and hesperidin) for enhanced efficacy in vascular conditions.

Regional Variations: Rutin-containing medications and supplements have been particularly popular in European countries, especially Germany, France, and Italy, where phytomedicine has a strong tradition. In contrast, awareness and use in North America have been more limited until recently.

Integration With Conventional Medicine: In many European countries, rutin preparations are prescribed by physicians and may be partially covered by health insurance for specific indications. In other regions, they are primarily used as complementary or alternative therapies.

1842: First isolation of rutin from Ruta graveolens, 1940s: Elucidation of rutin’s complete chemical structure, 1940s: Brief classification as ‘Vitamin P’ along with other flavonoids, 1950s: First standardized commercial preparations for medical use, 1970s: Development of semi-synthetic rutin derivatives with improved bioavailability, 1990s: Increased understanding of molecular mechanisms of action, 2000s: Expansion of research into metabolic, neurological, and anticancer applications, 2010s: Development of enhanced bioavailability formulations

Early Sources: Initial commercial production relied on extraction from rue (Ruta graveolens) and related plants.

Buckwheat Transition: By the 1950s, buckwheat became the primary commercial source due to its high rutin content and ease of cultivation.

Extraction Methods: Early extraction methods used simple solvent extraction with alcohol or water. More sophisticated methods using selective solvents and purification techniques developed over time.

Synthetic Approaches: While total chemical synthesis of rutin has been achieved, it has not been commercially viable compared to extraction from natural sources.

Rutin has moderate evidence supporting its use for vascular conditions, particularly chronic venous insufficiency and related disorders. There is emerging evidence for its potential benefits in metabolic disorders, neuroprotection, and anti-inflammatory applications. Most research consists of in vitro and animal studies, with a more limited number of human clinical trials. The quality of available clinical studies varies, with many being small-scale or of short duration.

Clinical trial evaluating rutin in combination with standard therapy for diabetic neuropathy (NCT04567498), Study of rutin supplementation for mild cognitive impairment in elderly adults (ISRCTN15483459), Investigation of rutin for exercise-induced oxidative stress in athletes (NCT03985722)

Long-term safety and efficacy data beyond 12 months of treatment, Optimal dosing strategies for different conditions, Comparative effectiveness studies against other treatments for vascular and metabolic conditions, Well-designed clinical trials for emerging applications such as neuroprotection and metabolic disorders, Studies on enhanced bioavailability formulations and their clinical outcomes, Research on potential synergistic effects with other flavonoids and antioxidants