Report on Isoquercetin (DB12665): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Isoquercetin (DrugBank ID: DB12665), a naturally occurring flavonoid glycoside, represents a molecule of significant interest at the intersection of pharmaceuticals, nutraceuticals, and functional foods. Its primary identity is not that of a direct therapeutic agent but rather as a highly effective prodrug, or oral delivery system, for its more famous aglycone, quercetin. The core value proposition of Isoquercetin lies in its superior pharmacokinetic profile; the presence of a glucose moiety facilitates active transport in the small intestine, leading to significantly greater bioavailability and higher plasma and tissue concentrations of quercetin compared to the administration of quercetin itself. This enhanced delivery unlocks the in vivo potential of quercetin's well-documented pleiotropic biological activities.

The pharmacodynamic profile of Isoquercetin, mediated by its conversion to quercetin, is characterized by a multi-target mechanism of action. It exhibits potent antioxidant effects by directly scavenging reactive oxygen species and bolstering endogenous defense systems. Its anti-inflammatory properties are linked to the modulation of key signaling pathways such as NF-κB, while its antithrombotic activity involves the inhibition of targets like protein disulfide isomerase (PDI) and platelet aggregation. Direct inhibitory action on enzymes such as Aldo-keto reductase family 1 member B1 (AKR1B1) and Angiotensin-Converting Enzyme (ACE) provides a molecular basis for its potential in managing complications of diabetes and hypertension, respectively.

The clinical development of Isoquercetin is focused on conditions where its anti-inflammatory and antithrombotic effects are most relevant, including the prevention of venous thromboembolism (VTE) in cancer patients and managing thromboinflammation in sickle cell disease. While clinical trials have consistently demonstrated an excellent safety profile with minimal adverse effects and no increased bleeding risk, efficacy results have been mixed. Studies have often shown modulation of relevant biological markers without always achieving the designated primary clinical endpoints, suggesting a need for refined trial designs, dosing strategies, and endpoint selection. Its most promising clinical application appears to be as a supportive care agent, used adjunctively to mitigate the side effects of primary therapies (e.g., fatigue in sunitinib-treated cancer patients) or to manage disease-related complications.

Commercially and regulatorily, Isoquercetin exhibits a unique dual status. It is pursued as an investigational new drug for specific therapeutic indications while simultaneously being marketed as a dietary supplement and food ingredient. A key innovation, Enzymatically Modified Isoquercitrin (EMIQ), a more water-soluble and even more bioavailable form, has achieved Generally Recognized as Safe (GRAS) status from the U.S. Food and Drug Administration (FDA) for use as an antioxidant in certain foods. This bifurcated strategy highlights Isoquercetin's position as a case study in leveraging modern formulation science to overcome the traditional limitations of natural compounds, positioning it as a versatile molecule with established value in the nutraceutical market and continued, albeit challenging, potential in pharmaceutical development.

Chemical Identity and Physicochemical Properties

A precise understanding of Isoquercetin's chemical and physical nature is fundamental to interpreting its biological behavior, formulation challenges, and therapeutic potential. This section delineates its nomenclature, structural characteristics, and key physicochemical properties.

Nomenclature and Identifiers

Isoquercetin is known by several names, which can sometimes lead to ambiguity in the scientific literature. The terms Isoquercetin and Isoquercitrin are frequently used interchangeably to refer to the same compound identified by CAS Number 482-35-9.[1] However, a subtle chemical distinction can be made, as some databases reserve "Isoquercitrin" for the glucofuranoside form (PubChem CID 5280459, CAS 21637-25-2), while "Isoquercetin" refers to the glucopyranoside form (PubChem CID 5280804, CAS 482-35-9).[4] For the purposes of this report, which focuses on DrugBank entry DB12665, Isoquercetin refers to the glucopyranoside structure, which is the predominant form associated with CAS 482-35-9.

Its systematic IUPAC name is 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-3-oxychromen-4-one.[2] A comprehensive list of synonyms includes Quercetin 3-O-glucopyranoside, Quercetin-3-glucoside, Hirsutrin, Isotrifoliin, and the National Service Center designation NSC115918.[1] To facilitate accurate cross-referencing across chemical, biological, and regulatory databases, its key identifiers are consolidated in Table 1.

Table 1: Chemical and Physical Identifiers for Isoquercetin

Identifier Type	Value	Source(s)
DrugBank ID	DB12665	3
CAS Number	482-35-9	6
PubChem CID	5280804	3
UNII	6HN2PC637T	1
ChEBI ID	CHEBI:68352	3
InChIKey	OVSQVDMCBVZWGM-QSOFNFLRSA-N	1
SMILES	C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O[C@H]4C@@HO)O)O

Molecular and Chemical Structure

Isoquercetin is a small molecule with the chemical formula $C_{21}H_{20}O_{12}$. Its average molecular weight is approximately 464.38 g/mol (or 464.3763 Da), with a monoisotopic mass of 464.095476104 Da.

Structurally, it belongs to the flavonoid class of polyphenols, specifically categorized as a flavonol. Its core structure consists of a C6-C3-C6 carbon skeleton, comprising two phenolic rings (A and B) connected by a three-carbon heterocyclic C ring. The defining feature of Isoquercetin is its classification as a flavonoid-3-O-glycoside. This signifies that the aglycone, quercetin, is linked via an O-glycosidic bond at the C3 position of the C ring to a sugar moiety, which in this case is a $\beta$-D-glucopyranosyl residue. This glycosidic linkage is the critical structural element responsible for its distinct pharmacokinetic properties compared to its parent aglycone. Analytical identification of the molecule is supported by spectral data, including LC-MS/MS spectra acquired in both positive and negative ionization modes.

Physicochemical Properties

Isoquercetin typically presents as a light yellow to yellow crystalline solid or powder. Its physical properties significantly influence its formulation and biological activity.

• Solubility: It exhibits limited solubility in aqueous media, being described as slightly soluble in water. Its solubility is higher in organic solvents, with reported values of 10 mg/ml in both dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), but only 0.3 mg/ml in phosphate-buffered saline (PBS) at pH 7.2. This poor water solubility is a major obstacle to its formulation and bioavailability, a challenge that has directly driven the development of more soluble derivatives. The innovation of Enzymatically Modified Isoquercitrin (EMIQ), a highly water-soluble oligoglucoside mixture, is a direct consequence of the need to overcome the inherent solubility limitations of the native molecule.
• Melting Point: The melting point is reported in the range of 230–242 °C.
• Stability: The compound is noted to be hygroscopic, meaning it readily absorbs moisture from the air. Despite this, it is considered stable enough for shipment under ambient temperature conditions. For long-term storage, conditions of 0-4 °C (short-term) or -20 °C (long-term) in a dry, dark environment are recommended.
• Predicted Properties: Computational models predict a strongest acidic pKa value around 6.17–6.37 and a LogP (octanol-water partition coefficient) of approximately 0.47, indicating a relatively hydrophilic character compared to many other flavonoids, yet still possessing limited water solubility.

Pharmacodynamics: Biological Activity and Mechanisms of Action

The biological effects of Isoquercetin are multifaceted, stemming from both direct interactions with molecular targets and, more significantly, from the broad-spectrum activities of its primary metabolite, quercetin. Its pharmacodynamic profile is best understood by first recognizing its role as a prodrug that enhances the systemic delivery of quercetin.

Primary Mechanism: A Prodrug for Quercetin

The central tenet of Isoquercetin's pharmacology is its function as a highly bioavailable precursor to quercetin. While in vitro and ex vivo assays often show Isoquercetin to be less potent than its aglycone, quercetin, this relationship is inverted in vivo. In a physiological system, orally administered Isoquercetin is equally or more active than quercetin. This apparent paradox is resolved by its superior pharmacokinetics; Isoquercetin's glycoside structure facilitates more efficient absorption, ultimately delivering a higher concentration of active quercetin metabolites to target tissues throughout the body. Therefore, its primary mechanism of action is to serve as an efficient delivery vehicle for quercetin.

Direct Molecular Targets

Despite its role as a prodrug, Isoquercetin has been identified as a direct inhibitor of at least two key human enzymes.

• Aldo-keto reductase family 1 member B1 (AKR1B1): Isoquercetin is an inhibitor of AKR1B1, also known as aldose reductase. This enzyme is the rate-limiting step in the polyol pathway, which converts glucose into sorbitol. Under hyperglycemic conditions, such as in diabetes mellitus, the overactivation of this pathway leads to the intracellular accumulation of sorbitol, creating osmotic stress that contributes to the pathogenesis of diabetic complications like neuropathy, nephropathy, and retinopathy. By inhibiting AKR1B1, Isoquercetin has a direct molecular mechanism through which it could mitigate the long-term tissue damage associated with diabetes.
• Angiotensin-Converting Enzyme (ACE): Isoquercetin is also listed as an inhibitor of ACE. ACE plays a pivotal role in the renin-angiotensin system (RAS) by catalyzing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor that elevates blood pressure. ACE also degrades bradykinin, a vasodilator. Inhibition of ACE is a cornerstone of modern therapy for hypertension and heart failure. This direct inhibitory action on ACE provides a clear molecular basis for the cardioprotective and potential antihypertensive effects attributed to Isoquercetin and its metabolite, quercetin.

Broad Pharmacological Effects (Mediated by Quercetin)

Following its absorption and conversion, the resulting quercetin exerts a wide range of biological effects that define Isoquercetin's therapeutic potential. The molecule's ability to influence numerous targets and pathways simultaneously is a defining characteristic. This pleiotropic activity explains its relevance across a wide array of disease models, from cancer to cardiovascular disease to viral infections. However, this lack of specificity presents a challenge for classical drug development, which typically favors single, high-potency targets. This "multi-target" profile may be better suited for managing complex, multifactorial conditions or for use as a general health-promoting supplement rather than as a precision therapeutic.

• Antioxidant Activity: Quercetin is a powerful antioxidant that restores oxidative homeostasis. Its mechanism is threefold:

1. Direct Radical Scavenging: The multiple hydroxyl groups on its phenolic rings allow it to readily donate electrons and protons, neutralizing damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS).
2. Metal Chelation: It chelates transition metal ions like iron ($Fe^{2+}$) and copper ($Cu^{2+}$), preventing them from participating in Fenton-type reactions that generate highly reactive hydroxyl radicals.
3. Support of Endogenous Systems: It enhances the body's own antioxidant defenses by upregulating the expression and activity of enzymes such as glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and activating the Nrf2/ARE antioxidant pathway. This comprehensive antioxidant action underpins its observed neuroprotective, hepatoprotective, and cardioprotective effects.

• Anti-inflammatory and Immunomodulatory Activity: Isoquercetin and quercetin modulate key inflammatory pathways. They have been shown to inhibit the nuclear factor-κB (NF-κB) signaling system, a master regulator of the inflammatory response. Furthermore, they stabilize mast cells, inhibiting the release of histamine and other pro-inflammatory mediators, which explains their traditional use in managing allergic reactions.
• Antithrombotic and Cardiovascular Effects: Isoquercetin is classified as an antithrombotic agent. Its effects are mediated through the inhibition of P-selectin, platelet activating factor, and platelet aggregation. A key molecular target in this pathway is protein disulfide isomerase (PDI), an enzyme critical for thrombus formation. Clinical data from a trial in sickle cell disease patients confirmed that Isoquercetin treatment significantly reduced whole blood coagulation and collagen-induced platelet aggregation.
• Antineoplastic Activity: Isoquercetin has demonstrated antineoplastic and antiproliferative properties in various preclinical models, including against colon, lung, and breast cancer cell lines. Its anticancer mechanisms are multi-targeted and include the induction of apoptosis (programmed cell death) and excessive autophagy, often through modulation of the PI3K/Akt/mTOR signaling pathway.
• Antiviral Activity: A growing body of evidence supports the broad-spectrum antiviral activity of Isoquercetin. It has shown efficacy in reducing viral titers and infection rates for a range of viruses, including influenza H5N1, Zika, Ebola, and dengue virus. Its potential mechanisms include inhibiting viral entry into host cells and interfering with viral replication machinery. This has led to significant interest in its potential as a prophylactic or therapeutic agent for viral respiratory illnesses, including COVID-19.

Pharmacokinetics: The Advantage of Glycosylation

The pharmacokinetic profile of Isoquercetin is arguably its most important characteristic, as it explains the molecule's primary therapeutic advantage over its aglycone, quercetin. The processes of absorption, distribution, metabolism, and excretion (ADME) are defined by the presence of the glucose moiety, which transforms a poorly absorbed compound into an efficiently delivered one.

Absorption

The key to Isoquercetin's enhanced bioavailability lies in its unique mechanism of intestinal absorption. While quercetin aglycone, a lipophilic molecule, relies on slow and inefficient passive diffusion across the gut wall, Isoquercetin leverages an active transport system. The glucose portion of the molecule allows it to be recognized and transported by the sodium-dependent glucose transporter 1 (SGLT-1), a highly efficient transporter located on the brush border membrane of intestinal enterocytes.

Once transported to the mucosal surface or into the cell, Isoquercetin is rapidly metabolized. Enzymes in the small intestine, primarily lactase phlorizin hydrolase (LPH) on the cell surface and cytosolic $\beta$-glycosidase within the cell, cleave the glycosidic bond. This process, known as deglycosylation, releases the quercetin aglycone, which is then readily absorbed into the enterocyte. This active uptake and rapid conversion mechanism allows for a much faster and more complete absorption compared to quercetin alone. This process provides a clear blueprint for overcoming the bioavailability challenges of many natural polyphenols: utilizing a naturally occurring glycoside to hijack an endogenous nutrient transporter represents a highly effective strategy for enhancing oral delivery.

Distribution

After absorption and initial metabolism in the intestine, quercetin and its conjugates enter the portal circulation and are transported to the liver, where further metabolism occurs. From the liver, these metabolites are released into systemic circulation and distributed throughout the body.

Comparative animal studies have unequivocally demonstrated the superiority of Isoquercetin in delivering quercetin to the body. Oral administration of Isoquercetin results in two- to three-fold higher concentrations of quercetin metabolites in plasma and two- to five-fold higher concentrations in tissues compared to an equivalent dose of quercetin aglycone.

The tissue distribution is not uniform, which has significant therapeutic implications. The highest concentrations of quercetin metabolites are consistently found in the lungs, followed by the liver and kidneys. This preferential accumulation in pulmonary tissue provides a strong rationale for investigating Isoquercetin in respiratory diseases. Its natural distribution pattern targets the very organ system where its anti-inflammatory and antiviral effects could be most beneficial, giving it a distinct advantage over other flavonoids that may not concentrate as effectively in the lungs. In the brain, the highest levels are observed in the cerebellum.

Metabolism

Isoquercetin undergoes extensive biotransformation, and very little of the intact glycoside is found in systemic circulation. The metabolic cascade involves several key steps:

1. Deglycosylation: As described, the initial and most critical step is the removal of the glucose moiety in the small intestine to yield quercetin.
2. Phase II Conjugation: The liberated quercetin is then subject to extensive phase II metabolism in both the intestinal cells and the liver. This involves conjugation with glucuronic acid (glucuronidation) and sulfate groups (sulfation).
3. Methylation: O-methylation of the hydroxyl groups on the quercetin backbone also occurs, forming derivatives such as isorhamnetin (3'-O-methyl-quercetin).

The final circulating forms of the compound in the bloodstream are predominantly glucuronidated, sulfated, and methylated conjugates of quercetin.

Comparative Bioavailability: Isoquercetin vs. Quercetin

The culmination of its unique absorption and metabolism is a dramatic improvement in bioavailability. This is the central pharmacokinetic advantage of Isoquercetin. Data from multiple studies across different species consistently confirm this superiority, as summarized in Table 2.

Table 2: Comparative Pharmacokinetic Parameters of Isoquercetin vs. Quercetin

Parameter	Reported Value (Isoquercetin vs. Quercetin Aglycone)	Species / Study Type	Source(s)
Peak Plasma Concentration ($C_{max}$)	1.7 to 10-fold greater	Rats, Dogs, Pigs, Humans
Area Under the Curve (AUC)	1.8 to 6-fold greater	Rats, Dogs, Pigs, Humans
Time to Peak Concentration ($T_{max}$)	< 40 minutes (for Isoquercetin) vs. 2-4 hours (for Quercetin)	Humans
Tissue Metabolite Levels	2 to 5-fold higher	Rats

Furthermore, advanced formulations have pushed these boundaries even further. Enzymatically Modified Isoquercitrin (EMIQ) is reported to have a bioavailability approximately 17 times that of quercetin aglycone, while the branded ingredient SunActive® IsoQ claims a 25-fold greater bioavailability. This demonstrates that formulation science can build upon the natural advantages of Isoquercetin to achieve even greater levels of systemic exposure.

Clinical Development Landscape

The translation of Isoquercetin from a preclinical compound to a human therapeutic is an ongoing process characterized by investigations into several disease areas. The clinical trial landscape reflects a strategy focused on leveraging its core anti-inflammatory, antithrombotic, and supportive care properties.

Overview of Investigational Areas

Clinical research on Isoquercetin has primarily targeted pathologies where thromboinflammation and oxidative stress play a key role. The main therapeutic areas of investigation include:

• Oncology: Primarily as an adjunctive therapy in Renal Cell Carcinoma and for the prevention of Venous Thromboembolism (VTE) in patients with pancreatic and colorectal cancer.
• Hematology: Management of thrombo-inflammatory complications in Sickle Cell Disease.
• Cardiovascular Disease: Prevention of platelet aggregation, although a key trial in this area was withdrawn.
• Infectious Disease: An investigational study in combination with another agent for moderate to severe COVID-19.

Key Clinical Trials Analysis

A summary of the most significant clinical trials provides a snapshot of the current state of development for Isoquercetin. This is detailed in Table 3.

Table 3: Summary of Key Clinical Trials for Isoquercetin

NCT Identifier	Title / Purpose	Condition(s)	Phase	Status	Intervention(s)	Source(s)
NCT06861088	The Effect of Isoquercetin on Thromboembolic Events in Patients with Metastatic Pancreatic Cancer	Venous Thromboembolism (VTE)	3	Not Yet Recruiting	Isoquercetin
NCT02446795	Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-line Sunitinib	Cancer of the Kidney / Renal Cell Carcinoma	1 / 2	Unknown Status	Isoquercetin, Sunitinib
NCT04514510	Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease	Sickle Cell Disease	Not Applicable	Completed	Isoquercetin
NCT04622865	Masitinib Combined With Isoquercetin and Best Supportive Care in Hospitalized Patients With Moderate and Severe COVID-19	COVID-19	Not Applicable	Investigational	Isoquercetin, Masitinib
NCT02866448	Impact of isoQUercetin and Aspirin on Platelet Function	Cardiovascular Disease	Not Available	Withdrawn	Isoquercetin, Acetylsalicylic acid
NCT01722669	Pharmacokinetic and Pharmacodynamic Study of Quercetin and Isoquercetin	Healthy Volunteers, Antiphospholipid Antibodies	Not Applicable	Completed	Isoquercetin, Quercetin

A notable pattern emerges from the clinical data, particularly from the completed trial in sickle cell disease (NCT04514510). In this study, Isoquercetin failed to meet its primary endpoint, a reduction in the plasma biomarker soluble P-selectin. However, the drug demonstrated clear biological activity, significantly reducing several secondary mechanistic biomarkers, including whole-blood coagulation, collagen-induced platelet aggregation, and PDI reductase activity. This disconnect—where the drug is active but doesn't impact the chosen primary endpoint—suggests that future clinical strategies may require re-evaluation. The issue could lie in insufficient dosing, short treatment duration, or the selection of a primary endpoint that is not optimally aligned with the drug's specific mechanism of action. The planned Phase 3 trial (NCT06861088) focusing on the incidence of actual thromboembolic events, rather than a surrogate biomarker, represents a more direct and potentially more fruitful approach to demonstrating clinical efficacy.

Another critical observation is the consistent positioning of Isoquercetin as a supportive or adjunctive agent, rather than a standalone monotherapy. In the renal cancer trial (NCT02446795), it is used to mitigate the side effect of fatigue from sunitinib treatment. In the COVID-19 study, it is combined with masitinib. In the sickle cell trial, it is administered to patients already on standard-of-care therapy to manage a complication of the disease. This suggests that investigators and developers recognize its potential value lies in complementing existing treatment regimens. This strategy leverages Isoquercetin's excellent safety profile, making it an attractive add-on to more toxic or less comprehensive therapies. Pursuing approval as a supportive care agent represents a more pragmatic and achievable clinical and commercial pathway than attempting to establish it as a first-line monotherapy for a major disease.

Safety, Toxicology, and Drug Interaction Profile

A comprehensive evaluation of Isoquercetin's safety profile is essential for its development as both a therapeutic agent and a widely consumed supplement. The available data from clinical, preclinical, and in vitro studies indicate a high degree of safety, though potential for drug interactions requires careful consideration.

Clinical Safety and Tolerability

Human clinical trials have consistently demonstrated that Isoquercetin is safe and well-tolerated. In a randomized, double-blind, placebo-controlled trial in adults with sickle cell disease (NCT04514510), a daily dose of 1,000 mg for four weeks was found to be safe. Critically, none of the 21 adverse events or 14 serious adverse events reported were attributed to the study drug, and there was no observed increase in bleeding complications. This latter point is particularly important for an agent with antithrombotic properties, as it distinguishes it from conventional anticoagulants that carry a significant bleeding risk.

The acceptable daily intake (ADI) for isoquercitrin has been estimated to be 5.4 mg/kg of body weight per day. Side effects associated with high oral doses of its metabolite, quercetin, are generally mild and infrequent, including headache or a tingling sensation in the extremities. High-dose intravenous administration of quercetin has been linked to kidney toxicity in cancer patients, but this is not considered relevant for oral use at standard supplemental doses.

Preclinical Toxicology

Preclinical studies support the strong safety profile observed in humans.

• Acute Toxicity: The compound exhibits very low acute toxicity. The median lethal dose ($LD_{50}$) in mice following intraperitoneal injection was greater than 5 g/kg, a very high dose indicating a wide safety margin.
• Genotoxicity: The genotoxicity profile of Isoquercetin is nuanced and requires careful interpretation. In vitro, isoquercitrin tested positive in some assays, specifically the bacterial reverse mutation (Ames) test and a chromosomal aberration assay using Chinese Hamster Ovary (CHO) cells. However, this was contradicted by a comprehensive battery of in vivo tests, all of which were negative. These included micronucleus and comet assays in both rats and mice, as well as Muta™ Mouse mutation assays across multiple tissues. This pattern is common for flavonoids and is generally understood to reflect the limitations of in vitro systems, which lack the complex metabolic and detoxification machinery present in a whole organism. In vivo, mammals efficiently conjugate and excrete flavonoids like quercetin through Phase II metabolic pathways, effectively neutralizing any potential genotoxic threat before it can cause DNA damage. Therefore, the weight of evidence from the more physiologically relevant in vivo studies suggests that Isoquercetin does not pose a genotoxic risk to humans.
• Carcinogenicity: A 24-month carcinogenicity study in rats using high dietary concentrations (up to 5.0%) of the related compound alpha-glycosyl isoquercitrin (AGIQ) found a statistically significant increase in malignant gliomas in high-dose females. However, a subsequent review by an expert panel of neuropathologists concluded that these were rare, spontaneous, rat-specific neoplasms (malignant microglial tumors) that could not be definitively attributed to AGIQ exposure and have limited relevance for predicting human cancer risk.

Drug Interactions

The potential for drug-drug interactions is a significant consideration, primarily driven by the metabolic actions of quercetin.

• Metabolic Interactions (Cytochrome P450): Quercetin is known to inhibit several key drug-metabolizing enzymes in the cytochrome P450 (CYP) family, including CYP3A4, CYP2C8, CYP2C9, and CYP2D6. This can slow the metabolism of numerous prescription drugs, potentially increasing their plasma concentrations and the risk of adverse effects.
• Transporter Interactions (P-glycoprotein): Quercetin also interacts with the P-glycoprotein (P-gp/MDR1) efflux transporter, a protein that actively pumps many drugs out of cells and is a key factor in drug disposition and resistance. By inhibiting P-gp, quercetin can increase the absorption and decrease the clearance of P-gp substrate drugs, such as digoxin, cyclosporine, and various chemotherapeutic agents. This interaction profile could be leveraged therapeutically; for instance, many chemotherapy drugs are substrates for both CYP3A4 and P-gp. Co-administration of Isoquercetin could therefore act as a pharmacokinetic booster, increasing the intracellular concentration and efficacy of these anticancer agents and potentially helping to overcome multidrug resistance. This suggests a novel application for Isoquercetin as a chemosensitizing agent in oncology.
• Pharmacodynamic Interactions:
• Anticoagulants and Antiplatelets: Due to its intrinsic antiplatelet and anticoagulant effects, there is a theoretical risk of additive effects when combined with medications like warfarin or aspirin, potentially increasing bleeding risk. Caution is advised, although at least one clinical report found no significant changes in bleeding parameters when quercetin was co-administered.
• Antihypertensive Drugs: Quercetin can lower blood pressure. When taken with other antihypertensive medications, it could lead to an excessive drop in blood pressure (hypotension).
• Antibiotics: There is evidence that quercetin may antagonize the antibacterial effects of fluoroquinolone antibiotics, such as ciprofloxacin.

Regulatory and Commercial Status

Isoquercetin occupies a unique position in the global market, navigating parallel regulatory pathways as both an investigational pharmaceutical and a commercial nutraceutical and food ingredient. This dual-track strategy reflects its versatile nature and broad applicability.

United States (FDA)

In the United States, the regulatory status of Isoquercetin is multifaceted and depends on its form and intended use.

• Dietary Supplement and Food Ingredient: Isoquercetin is widely available as an ingredient in dietary supplements. However, the FDA strictly regulates the claims made for such products. The agency has issued warning letters to companies marketing supplements containing quercetin with explicit disease treatment or prevention claims (e.g., "inhibits the release of histamines," "prevents alcohol-induced liver damage"), deeming these products to be unapproved new drugs. A more formalized status has been achieved for Enzymatically Modified Isoquercitrin (EMIQ), a proprietary, highly bioavailable form. This specific substance was the subject of GRAS Notice No. GRN000220, and the FDA responded with a "no questions" letter, effectively affirming its status as Generally Recognized as Safe (GRAS). This GRAS status is specifically for the use of EMIQ as an antioxidant to protect flavors and colors in designated food categories, including beverages, fruit juices, and bakery products, at levels of 75–150 mg/kg, and in chewing gum at levels up to 1500 mg/kg. This distinction is critical: the favorable regulatory status applies to the specific, technologically advanced EMIQ formulation, not to generic Isoquercetin, highlighting the importance of manufacturing processes and intellectual property in the commercialization of nutraceuticals.
• Investigational Drug: Parallel to its use as a supplement, Isoquercetin is being developed as a pharmaceutical under Investigational New Drug (IND) applications filed with the FDA. It is currently in clinical trials for specific medical indications, but it has not received a New Drug Application (NDA) approval and is not an approved prescription drug.

Europe (EMA) and Australia (TGA)

• Europe (EMA): The provided information does not indicate that Isoquercetin has undergone a formal marketing authorisation review by the European Medicines Agency (EMA) for use as a medicinal product. It is, however, listed in the European Commission's cosmetic ingredient database (CosIng) for use as an antioxidant in cosmetic products. It is also registered with the European Chemicals Agency (ECHA).
• Australia (TGA): Australia's Therapeutic Goods Administration (TGA) permits quercetin (as the active moiety) as an ingredient in "listed" medicines, which are equivalent to dietary supplements in the U.S. Regulatory amendments have explicitly made preparations containing quercetin eligible for listing on the Australian Register of Therapeutic Goods (ARTG). Consequently, several products containing quercetin dihydrate are available on the Australian market as listed medicines.

Commercialization and Branding

Isoquercetin is commercially available in several forms. It is sold as a high-purity chemical for research purposes by numerous scientific supply companies. In the consumer market, it is primarily sold as a key ingredient in branded dietary supplements, often in enhanced-bioavailability formulations that represent significant commercial and technological assets. Key branded ingredients include:

• SunActive® IsoQ: A proprietary, water-soluble formulation of Isoquercetin that claims a 25-fold increase in bioavailability compared to standard quercetin.
• Alpha-Glycosyl Isoquercitrin: The branded name for EMIQ, marketed exclusively by Integrative Therapeutics. It is promoted as having 3 times the bioavailability of standard isoquercetin and nearly 18 times that of quercetin aglycone.
• Isoquercetin w/Bioperine®: A formulation from Pure Encapsulations that combines Isoquercetin with piperine (from black pepper extract) to inhibit metabolic breakdown and enhance the duration of action.

Sourcing, Synthesis, and Formulation

The availability of Isoquercetin for research, clinical trials, and commercial products depends on reliable methods of sourcing and production, as well as advanced formulation techniques to maximize its biological potential.

Natural Sources

Isoquercetin is a secondary metabolite found ubiquitously throughout the plant kingdom. It is present in many common edible plants, making it a natural component of the human diet. Prominent dietary and botanical sources include:

• Fruits such as mangoes (Mangifera indica) and custard apples (Annona squamosa).
• Vegetables, most notably onions (Allium cepa).
• Beverages like tea (Camellia sinensis).
• Medicinal plants and herbs, including Noble rhubarb (Rheum nobile), Ginkgo biloba, Moringa oleifera, and Lepisorus contortus.

Extraction and Synthesis

For commercial and pharmaceutical use, Isoquercetin is obtained through extraction from plant materials or through a more efficient semi-synthetic process.

• Extraction: Traditional extraction methods like maceration and Soxhlet extraction are being replaced by modern, more efficient "green" technologies. Techniques such as Ultrasound-Assisted Extraction (UAE) and Microwave-Assisted Extraction (MAE) use physical energy to disrupt plant cell walls, allowing for faster extraction with lower solvent consumption. UAE, for example, has been specifically optimized to maximize the yield of Isoquercetin from the plant Ephedra alata.
• Semi-Synthesis from Rutin: The most economically significant method for large-scale production of Isoquercetin is the enzymatic conversion of rutin (quercetin-3-O-rutinoside). Rutin is another abundant and relatively inexpensive flavonoid. The enzyme $\alpha$-L-rhamnosidase is used to selectively cleave the rhamnose sugar from the rutinose disaccharide attached to quercetin, leaving behind the desired Isoquercetin (quercetin-3-O-glucoside). This biotransformation process is the economic engine of the Isoquercetin supply chain, allowing for the cost-effective production of a high-value compound from a readily available, lower-cost starting material.

Advanced Formulations

Given the inherent limitations of native Isoquercetin's solubility, significant innovation has focused on creating advanced formulations with superior physicochemical and pharmacokinetic properties.

• Enzymatically Modified Isoquercitrin (EMIQ): Also known as Alpha-Glycosyl Isoquercitrin (AGIQ), this is the most important commercial formulation. It is produced by taking Isoquercetin (often derived from rutin) and using enzymes to attach additional linear glucose units to the existing glucose moiety. The result is a mixture of quercetin oligoglucosides that is highly water-soluble and demonstrates markedly superior bioavailability compared to both quercetin and standard Isoquercetin.
• Bioavailability Enhancers: Another formulation strategy involves combining Isoquercetin with other natural compounds that inhibit its metabolic breakdown. For example, formulations containing Bioperine® (a standardized extract of piperine from black pepper) are designed to inhibit the UGT enzymes responsible for glucuronidating quercetin in the liver. By slowing this inactivation process, piperine can increase the plasma concentration and extend the duration of action of the active quercetin metabolites.

Expert Analysis and Future Outlook

Isoquercetin stands out from the vast landscape of flavonoid research not for its intrinsic potency, which is often less than its aglycone quercetin in vitro, but for its role as a solution to the central problem that has long plagued nutraceutical development: poor oral bioavailability. Its identity as a natural, highly efficient prodrug for quercetin defines its current value and future potential.

Synthesis of Findings

The comprehensive analysis of Isoquercetin reveals a compelling narrative. It is a naturally occurring glycoside whose primary function is to leverage the body's own glucose transport mechanisms to overcome the absorption bottleneck of quercetin. This results in significantly higher systemic exposure, particularly in key tissues like the lungs, thereby unlocking the in vivo efficacy of quercetin's broad pharmacodynamic actions. These actions—spanning antioxidant, anti-inflammatory, antithrombotic, and antiviral effects—are pleiotropic, making Isoquercetin a versatile agent but also one that lacks the target specificity favored in traditional pharmaceutical development.

Its clinical development reflects this duality. Trials have targeted complex, multifactorial conditions like thromboinflammation in cancer and sickle cell disease. While these studies have consistently affirmed its excellent safety profile, the efficacy signals have been modest or mixed, often demonstrating clear biological activity on mechanistic biomarkers without achieving designated primary endpoints. This suggests its most viable clinical niche may be as a supportive care agent—mitigating side effects or managing complications—rather than as a first-line monotherapy.

This clinical reality is mirrored in its commercial and regulatory strategy. A high-risk, long-term pharmaceutical development program is running in parallel with a highly successful, lower-risk nutraceutical track. The latter has been propelled by technological innovation, namely the creation of Enzymatically Modified Isoquercitrin (EMIQ), a formulation with superior solubility and bioavailability that has achieved GRAS status in the U.S. for specific food applications. This bifurcated approach allows for near-term revenue generation and market presence while pursuing the ultimate goal of pharmaceutical approval.

Future Research and Development Directions

To realize the full potential of Isoquercetin, future research and development should be strategically focused on areas that capitalize on its unique strengths.

• Refined Clinical Strategy: Future clinical trials should be designed to align with its established pharmacokinetic and pharmacodynamic profile.

1. Focus on Respiratory Diseases: Given its preferential accumulation in lung tissue, trials investigating its role in viral respiratory infections (e.g., influenza), chronic obstructive pulmonary disease (COPD), or acute respiratory distress syndrome (ARDS) are strongly warranted.
2. Investigate as a Chemosensitizing Agent: The documented inhibition of P-glycoprotein and CYP3A4 by its metabolite, quercetin, suggests a powerful hypothesis: Isoquercetin could be used to enhance the efficacy of existing chemotherapy drugs and overcome multidrug resistance in cancer. Trials designed to test this synergistic effect in oncology should be prioritized.
3. Embrace Preventative and Long-Term Trials: Its excellent safety profile and homeostatic-restoring mechanisms make it an ideal candidate for long-term, preventative studies in chronic diseases driven by oxidative stress and inflammation, such as cardiovascular disease and neurodegeneration.

• Continued Formulation Science: While EMIQ represents a significant advancement, further innovation in drug delivery could yield even greater benefits. Research into nanoparticle-based formulations or other targeted delivery systems could enhance tissue-specific accumulation and reduce the required dose, further improving its therapeutic index.
• Definitive Head-to-Head Human Trials: To guide clinical use and consumer choice, well-powered human clinical trials that directly compare the pharmacokinetic profiles and clinical outcomes of standard quercetin, Isoquercetin, and EMIQ are needed. Such studies would provide definitive data on the relative benefits of each form and establish optimal dosing strategies.

Final Conclusion

Isoquercetin is more than just another flavonoid; it is a paradigm of how a deep understanding of pharmacokinetics can transform a promising but poorly delivered natural compound into a viable therapeutic and commercial product. Its primary value is not its own biological activity, but its elegant solution to the delivery of its active metabolite, quercetin. While the path to securing approval as a mainstream prescription drug remains challenging, its proven safety, superior bioavailability, and the commercial success of its advanced formulations have already cemented its place in the high-value nutraceutical and functional food markets. The future trajectory of Isoquercetin will be determined by the ability of researchers and developers to design smarter clinical trials that play to its unique strengths and to continue innovating in formulation science to further optimize its delivery and unlock its full, system-wide health benefits.

Works cited

1. ISOQUERCITRIN | 482-35-9 - ChemicalBook, accessed October 23, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9419348.htm
2. Isoquercetin | CAS#482-35-9 | Flavonoid - MedKoo Biosciences, accessed October 23, 2025, https://www.medkoo.com/products/15206
3. Isoquercetin - Wikipedia, accessed October 23, 2025, https://en.wikipedia.org/wiki/Isoquercetin
4. Isoquercetin | C21H20O12 | CID 5280804 - PubChem - NIH, accessed October 23, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Isoquercetin
5. Isoquercitrin | C21H20O12 | CID 5484006 - PubChem - NIH, accessed October 23, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Isoquercitrin
6. Isoquercetin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 23, 2025, https://go.drugbank.com/drugs/DB12665
7. Isoquercetin (CAS 482-35-9) - Cayman Chemical, accessed October 23, 2025, https://www.caymanchem.com/product/24926/isoquercetin
8. Quercetin-3-o-glucopyranoside | CAS 482-35-9 | SCBT - Santa Cruz Biotechnology, accessed October 23, 2025, https://www.scbt.com/p/quercetin-3-o-glucopyranoside-482-35-9
9. Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize - Frontiers, accessed October 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.830205/full
10. LC-MS/MS Spectrum - LC-ESI-QTOF , negative (DB12665) - DrugBank, accessed October 23, 2025, https://go.drugbank.com/spectra/ms_ms/436974
11. LC-MS/MS Spectrum - LC-ESI-QTOF , positive (DB12665) - DrugBank, accessed October 23, 2025, https://go.drugbank.com/spectra/ms_ms/448096
12. Isoquercetin | CAS NO.:482-35-9 - GlpBio, accessed October 23, 2025, https://www.glpbio.com/isoquercetin.html
13. Enzymatically Modified Isoquercitrin: Production, Metabolism ..., accessed October 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9738368/
14. Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize - PMC - NIH, accessed October 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8924057/
15. Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize - Frontiers, accessed October 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.830205/epub
16. Isoquercitrin: pharmacology, toxicology, and metabolism - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/24680690/
17. Comparison of Quercetin and Isoquercitrin's Anti-Heart Failure Activity via MAPK Inflammatory Pathway and Caspase Apoptosis Pathway - MDPI, accessed October 23, 2025, https://www.mdpi.com/1424-8247/18/10/1447
18. Isoquercitrin: Pharmacology, toxicology, and metabolism | Request PDF - ResearchGate, accessed October 23, 2025, https://www.researchgate.net/publication/261219878_Isoquercitrin_Pharmacology_toxicology_and_metabolism
19. Alpha-Glycosyl Isoquercitrin - Pure Prescriptions, accessed October 23, 2025, https://pureprescriptions.com/product/alpha-glycosyl-isoquercitrin-integrative-therapeutics-inc/
20. Isoquercetin - Quercis Pharma - AdisInsight - Springer, accessed October 23, 2025, https://adisinsight.springer.com/drugs/800062037
21. Study Details | NCT04514510 | Fixed Dose Flavonoid Isoquercetin ..., accessed October 23, 2025, https://clinicaltrials.gov/study/NCT04514510
22. Pharmacokinetic and pharmacodynamic study of oral quercetin and isoquercetin in healthy adults and patients with hypercoagulable states. - ClinicalTrials.gov, accessed October 23, 2025, https://cdn.clinicaltrials.gov/large-docs/69/NCT01722669/Prot_SAP_000.pdf
23. Isoquercetin Lowers Several Thromboinflammatory Biomarkers in ..., accessed October 23, 2025, https://ashpublications.org/ashclinicalnews/news/7778/Isoquercetin-Lowers-Several-Thromboinflammatory
24. Isoquercetin for thromboinflammation in sickle cell disease: a randomized double-blind placebo-controlled trial - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/38157227/
25. Electronic structures of isoquercitrin and its pharmacokinetic exploration with Dengue virus 1 NS5 methyl transferase - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/39976905/
26. (PDF) Electronic structures of isoquercitrin and its pharmacokinetic exploration with Dengue virus 1 NS5 methyl transferase - ResearchGate, accessed October 23, 2025, https://www.researchgate.net/publication/389177822_Electronic_structures_of_isoquercitrin_and_its_pharmacokinetic_exploration_with_Dengue_virus_1_NS5_methyl_transferase
27. Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/35308240/
28. Bioavailability of Quercetin - Current Research in Nutrition and Food Science Journal, accessed October 23, 2025, https://www.foodandnutritionjournal.org/vol04nospl-issue-conf-october-2016/bioavailability-of-quercetin/
29. Pharmacokinetic comparison of quercetin, isoquercitrin, and quercetin-3-O-β-D-glucuronide in rats by HPLC-MS - PubMed Central, accessed October 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6440464/
30. Isoquercitrin provides better bioavailability than quercetin: Comparison of quercetin metabolites in body tissue and brain sections after six days administration of isoquercitrin and quercetin - ResearchGate, accessed October 23, 2025, https://www.researchgate.net/publication/235369243_Isoquercitrin_provides_better_bioavailability_than_quercetin_Comparison_of_quercetin_metabolites_in_body_tissue_and_brain_sections_after_six_days_administration_of_isoquercitrin_and_quercetin
31. Isoquercitrin provides better bioavailability than quercetin: comparison of quercetin metabolites in body tissue and brain sections after six days administration of isoquercitrin and quercetin - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/23346761/
32. comparison of quercetin metabolites in body tissue and brain secti - Ingenta Connect, accessed October 23, 2025, http://www.ingentaconnect.com/contentone/govi/pharmaz/2012/00000067/00000012/art00006?crawler=true
33. SunActive® IsoQ | NutriScience Innovations, LLC, accessed October 23, 2025, https://nutriscienceusa.com/product/sunactive-isoq/
34. Enzymatically modified isoquercitrin supplementation intensifies plantaris muscle fiber hypertrophy in functionally overloaded mice - PMC - PubMed Central, accessed October 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5581924/
35. Cardiovascular Disease Withdrawn Phase Trials for Isoquercetin (DB12665) - DrugBank, accessed October 23, 2025, https://go.drugbank.com/indications/DBCOND0028376/clinical_trials/DB12665?phase=&status=withdrawn
36. Venous Thromboembolism (VTE) Not Yet Recruiting Phase 3 Trials for Isoquercetin (DB12665) | DrugBank Online, accessed October 23, 2025, https://go.drugbank.com/indications/DBCOND0047323/clinical_trials/DB12665?phase=3&status=not_yet_recruiting
37. Cancer of the Kidney Unknown Status Phase 1 / 2 Trials for Isoquercetin (DB12665), accessed October 23, 2025, https://go.drugbank.com/indications/DBCOND0078568/clinical_trials/DB12665?phase=1%2C2&status=unknown_status
38. NCT01722669 | Quercetin PK/PD Study in Healthy Adults and Patients With Hypercoagulable States | ClinicalTrials.gov, accessed October 23, 2025, https://clinicaltrials.gov/study/NCT01722669
39. Quercetin Side Effects: What You Need to Know - Gaia Herbs, accessed October 23, 2025, https://www.gaiaherbs.com/blogs/seeds-of-knowledge/quercetin-side-effects
40. Quercetin: Side Effects, Dosage, and Interactions - Verywell Health, accessed October 23, 2025, https://www.verywellhealth.com/the-benefits-of-quercetin-89071
41. Quercetin: Generic, Supplement Uses, Warnings, Side Effects, Dosage - MedicineNet, accessed October 23, 2025, https://www.medicinenet.com/quercetin/article.htm
42. Comprehensive evaluation of the flavonol anti-oxidants, alpha ..., accessed October 23, 2025, https://focusontoxpath.com/comprehensive-evaluation-of-the-flavonol-anti-oxidants-alpha-glycosyl-isoquercitrin-and-isoquercitrin-for-genotoxic-potential/
43. Oral chronic toxicity and carcinogenicity study of alpha-glycosyl isoquercitrin (AGIQ) in Sprague Dawley rats - PubMed, accessed October 23, 2025, https://pubmed.ncbi.nlm.nih.gov/36773715/
44. QUERCETIN: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews, accessed October 23, 2025, https://www.webmd.com/vitamins/ai/ingredientmono-294/quercetin
45. Isoquercetin w/Bioperine® - Pure Encapsulations, accessed October 23, 2025, https://www.pureencapsulationspro.com/media/Isoquercetin-w_Bioperine.pdf
46. Indication-specific dosing for (quercetin), frequency-based adverse effects, comprehensive interactions, contraindications, pregnancy & lactation schedules, and cost information. - Medscape Reference, accessed October 23, 2025, https://reference.medscape.com/drug/quercetin-344495
47. QUERCETIN AND DRUGS: IS THERE INTERACTION? -, accessed October 23, 2025, https://www.quevir.it/en/approfondimenti-en/quercetin-and-drugs-is-there-interaction/
48. 3RD Day Nutraceuticals, LLC - 614321 - 07/08/2021 - FDA, accessed October 23, 2025, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/3rd-day-nutraceuticals-llc-614321-07082021
49. Enzymatically Modified Isoquercitrin in Supplements | Our Products | San-Ei Gen F.F.I., Inc., accessed October 23, 2025, https://www.saneigen.com/emiq2.html
50. FDA vs. EMA: Navigating Divergent Regulatory Expectations for Cell and Gene Therapies. What Biopharma Companies Need to Know | Cromos Pharma, accessed October 23, 2025, https://cromospharma.com/fda-vs-ema-navigating-divergent-regulatory-expectations-for-cell-and-gene-therapies-what-biopharma-companies-need-to-know/
51. Search | European Medicines Agency (EMA), accessed October 23, 2025, https://www.ema.europa.eu/en/search
52. Scientific guidelines | European Medicines Agency (EMA), accessed October 23, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-guidelines
53. ISOQUERCITRIN – Ingredient - COSMILE Europe, accessed October 23, 2025, https://cosmileeurope.eu/inci/detail/7538/isoquercitrin/
54. THERAPEUTIC GOODS AMENDMENT REGULATIONS 2003 (NO. 4) 2003 NO. 258 - 'classic' AustLII, accessed October 23, 2025, https://classic.austlii.edu.au/au/legis/cth/num_reg_es/tgar200342003n258434.html
55. Quercetin Complex (227647) - Therapeutic Goods Administration (TGA), accessed October 23, 2025, https://www.tga.gov.au/resources/artg/227647
56. Quercetin Advanced (380791) - Therapeutic Goods Administration (TGA), accessed October 23, 2025, https://www.tga.gov.au/resources/artg/380791
57. Tomorrows Nutrition Pro IsoQuercetin - Natural Healthy Concepts, accessed October 23, 2025, https://www.nhc.com/isoquercetin-by-tomorrows-nutrition-pro
58. Alpha-Glycosyl Isoquercitrin - 60 Vegetable Capsules - Integrative Therapeutics | PureFormulas, accessed October 23, 2025, https://www.pureformulas.com/product/alpha-glycosyl-isoquercitrin-by-integrative-therapeutics/1000010795
59. (PDF) Extracting Quercetin from Different Plant Sources, Purifying It Using Different Extraction Methods (Chemical, Physical, and Enzymatic), and Measuring Its Antioxidant Activity - ResearchGate, accessed October 23, 2025, https://www.researchgate.net/publication/386201634_Extracting_Quercetin_from_Different_Plant_Sources_Purifying_It_Using_Different_Extraction_Methods_Chemical_Physical_and_Enzymatic_and_Measuring_Its_Antioxidant_Activity
60. Extraction of Flavonoids From Natural Sources Using Modern Techniques - Frontiers, accessed October 23, 2025, https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.507887/full
61. Ultrasound-Assisted Extraction of Isoquercetin from Ephedra alata (Decne): Optimization Using Response Surface Methodology and In Vitro Bioactivities - PMC - PubMed Central, accessed October 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10045738/