Evaluating the Bioavailability of Isoquercetin

Nutraceutical Profile

By Jeremy Appleton, ND

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Quercetin glucosides are among the most common flavonoids in the human diet. They possess neuroprotective, cardioprotective, chemopreventive, antioxidant, anti-inflammatory, and anti-allergic properties. Quercetin (aglycone) is among the most popular flavonoid supplements. It is not, however, the dominant form appearing in nature, and its bioavailability is poor. Quercetin glucosides, such as isoquercetin, occur naturally and have the same therapeutic effects in vivo as quercetin (aglycone), but with better bioavailability. 


Flavonoids are a group of polyphenolic compounds, which are widely distributed throughout the plant kingdom. More than 5,000 flavonoid compounds have been identified. Many of them, including flavonols, have low toxicity in mammals and will be discussed in this profile. A great many flavonoids have demonstrated health-promoting effects in humans and in animal studies, which will also be addressed. Glycosides are molecules in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule.
Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides, which can be activated by enzyme hydrolysis. Dietary intake of flavonols is difficult to estimate accurately because values depend on assessment of feeding habits and flavonol content in foods. “Food sources, dietary intakes, and bioavailability of flavonols are also influenced by variations in plant type and growth, season, light, degree of ripeness, food preparation, and processing.” However, it has been estimated that adults in the United States typically consume about 1 gram of flavonoids per day.
Most of these flavonoids are in the form of glycosides with high molecular weight. The molecular weight and hydrophilicity of all glycosides has the potential to limit their absorption in the small intestine. Many flavonoids, such as rutin, pass unchanged into the large intestine, where they are hydrolyzed by microbially produced glycosidases, yielding quercetin aglycone and its sugar. However, absorption at this point in the intestine is quite limited. A limited number of clinical trials have been conducted on isolated flavonols (i.e., quercetin, rutin, hydroxyethylrutosides [a semi-synthetic form of rutin]). The most commonly accepted medical use of flavonols is in the maintenance of capillary integrity, for which the flavonols are applied topically, ingested, or taken by both routes concurrently.
Flavonols have also demonstrated neuroprotective,cardioprotective, chemopreventive, antioxidant, anti-inflammatory, and anti-allergic activity in numerous preclinical studies. Rutin and quercetin (aglycone), the most commonly used flavonol compounds in nutritional supplements, have poor bioavailability, which may lessen efficacy. Quercetin glucosides, however, have better bioavailability, resulting in potentially increased efficacy compared to the aglycone form. Although currently less widely available, quercetin glucosides show promise in overcoming some of the limitations of both quercetin aglycone and high–molecular weight rutinosides, expanding the efficacy and range of indications for this class of supplements.


Flavonoids are divided into several classes: flavonols, flavonones, flavones, flavanols, flavan-3-ols and isoflavones. These classifications are made according to the chemical composition of the compounds, specifically the positions of substitute groups present on the parent molecule. Flavonols are yellow, antioxidant pigments found in many flowers and plants. Yellow onion and curly kale are among the richest natural sources. Flavonols are also present in apple, broccoli, lettuce, tomato, grape, berries, tea, and red wine.
Rutin is found in the highest amounts in buckwheat, tomato, apricot, rhubarb, tea, celery, spinach, brussels sprouts and lemon. The rutin used in dietary supplements is typically derived from Dimorphandra spp. (Brazil) and Sophora japonica (Asia).
The flavonols rutin, quercetin, and isoquercetin are found not only in foods such as apple and onion, but in many medicinal plants, likely contributing to the medicinal qualities of a large number of botanical medicines. Some of the most commonly used plants containing these flavonoids include Aesculus hippocastanum (Horse chestnut), Ruscusaculeatus (Butcher’s Broom), Ginkgo biloba (Ginkgo), Hypericum perforatum (St. John’s Wort), Calendula officinalis (Pot marigold), Arctostaphylos uva ursi (Uva ursi), Equisetum arvense (Horsetail), Glycyrrhiza glabra (Licorice), Foeniculum vulgare (Fennel), Aspalathus linearis (Rooibos), Humulus lupulus (Hops), Tussilago farfara (Coltsfoot), Drosera rotundifolia (Sundew), Vaccinium myrtillus (Bilberry), Bupleurum chinense (Bupleurum), Fouquieria splendens (Ocotillo), and Morus spp. (Mulberry).10

Structure and Activity of Flavonols


Quercetin is a natural antioxidant, producing its antioxidative actions by inhibiting lipid peroxidation through blockade of the enzyme xanthine oxidase, chelating iron, and directly scavenging hydroxyl, peroxy, and superoxide radicals.11,12,13 Flavonols, including quercetin, also protect the antioxidative defense mechanism by increasing the absorption of vitamin C.14 Quercetin inhibits structural damage to proteins and the release and production of oxidative products generated by the respiratory burst in phagocytes.15,16 Quercetin is an aglycone, meaning that it lacks a glycoside side chain. In contrast, naturally occurring quercetin compounds are primarily glycosides, with only very small quantity occurring as an aglycone. Once absorbed from the gut, most quercetin compounds are metabolized to quercetin glucuronides, the primary metabolic form detected in plasma. As will be discussed later, isoquercetin (quercetin glucoside, a type of glycoside) is comparatively much more bioavailable than quercetin aglycone, the commonly available form as a supplement. Highly efficient hydrolysis of the glucoside chain in the absorptive endothelium of the small intestinal brush border yields quercetin aglycone within the enterocytes. This means that ingested isoquercetin itself does not reach the portal circulation; it enters the circulation either as quercetin aglycone or as a quercetin glucoside. Therefore, the therapeutic profile of isoquercetin is identical to that of quercetin. This article will therefore consider the therapeutic applications of isoquercetin together with those of quercetin.


As mentioned, quercetin does not principally occur in the form in which it is available as a dietary supplement (an aglycone). Instead, it occurs mostly as quercetin glycosides, with glucoside chains usually occurring at the 3 or 4 position of the pyrone ring.17 Isoquercetin is one of the naturally occurring glucosides of quercetin. It has the molecular formula C21H20O12 and a molar mass of 464.38 g/mol. It is also known as quercetin-3-O-glucoside, quercetin-3-O-ß-D-glucoside, and hirsutrin. Isoquercetin is also sometimes called isoquercitrin, a nearly identical quercetin-3-monoglucoside. Technically the two are different (isoquercetin has a pyranose ring whereas isoquercitrin has a furanose ring), but functionally the two molecules are indistinguishable. The literature often considers them as one and uses the names interchangeably, a convention followed hereafter in this article. 

Therapeutic Properties of Quercetin and its Glucosides: Indications and Clinical Applications


In a clinical study done by Edwards and colleagues, quercetin supplementation reduced blood pressure in hypertensive subjects.1 However, contrary to prior animal studies, there was no quercetin-evoked reduction in systemic markers of oxidative stress as was expected. The authors suggest the possibility of elevated oxidative stress in vascular and renal compartments of their hypertensive subjects, as has been seen in animal models of hypertension. They suggest that high oxidative stress in these compartments may have left little residual systemic effect of the antioxidants.
Quercetin supplementation has been shown to inhibit LDL oxidation in humans, though it does not appear to modify levels of LDL.2,3 Administration of quercetin glucoside to human subjects demonstrated that quercetin was bioavailable, with plasma concentrations attained in the range known to affect platelet function. Platelet aggregation was inhibited 30 and 120 min after ingestion of quercetin glucoside.4 Dietary flavonoids, such as quercetin and (-)-epicatechin, have also been shown to augment nitric oxide status and reduce endothelin-1 concentrations, thereby improving endothelial function.5

Blood Vessel Protection

One time-tested therapeutic indication for flavonols is the protection and restoration of blood vessel integrity. Endothelial oxidation, inflammation, and capillary fragility can set the stage for thrombosis and venous insufficiency. Isoquercetin has demonstrated dose-dependent protective effect against oxidative endothelial injury.6 It has also been shown to protect venular endothelium from inflammatory products released by activated blood platelets and polymorphonuclear granulocytes.7


The brain is particularly susceptible to oxidative damage because of its high utilization of oxygen, its high levels of unsaturated lipids and transition metals like iron, and its relatively inefficient antioxidant defenses.8 Reactive oxygen radicals and lipid peroxides have been implicated in the pathogenesis of neurological pathology, including brain trauma, ischemia, and neurodegenerative disorders. Agents capable of scavenging free radicals and inhibiting lipid peroxides, and thereby protecting neurons from oxidative injury, may help prevent and treat neurodegenerative disorders caused by oxidative stress. Flavonoids have demonstrated protection of the brain through their ability to modulate intracellular signals, promoting cellular survival.9
Food sources, dietary intakes, and bioavailability of flavonols are also influenced by variations in plant type and growth, season, light, degree of ripeness, food preparation, and processing.
Isoquercetin has demonstrated potential protective effects against oxidative neuronal injuries and brain ischemia. Dok-Go and colleagues found quercetin and its 3-methyl ether metabolite prevented xanthine oxidase-induced oxidative neuronal cell injury, scavenged free radicals, and inhibited lipid peroxidation. Quercetin 3-methyl ether, a methanolic extract of quercetin, was a more potent neuroprotectant than any of the other flavonoids tested.10 Heo and Lee observed that quercetin decreased oxidative stress-induced neuronal cell embrane damage more effectively than vitamin C.11 Quercetin has also attenuated carotid hypoperfusion injury to white matter in rats, suggesting protective effects against ischemic stroke.12 Krasteva and colleagues found that isoquercetin and related flavonoids increase cerebral blood flow and possess antihypoxic activity, and may account for of the application of flavonoid-containing botanical agents like Ginkgo biloba in memory loss.13 Further supporting this, quercetin and its glucosides have been shown to exert protective effects against cognitive decline related to aging, vascular dementia, and Alzheimer disease.14,15 Therapeutic effects in tardive dyskinesia in rats have also been noted.16

Antidepressant Activity

Early identification of therapeutic activity of isoquercetin came from studies in which the flavonol was extracted from Hypericum performatum (St. John’s wort). In fact, isoquercetin bears striking structural similarities to the main active constituents of St. John’s wort, particularly hyperoside.17 It has long been known that the antidepressant activity of the herb is due not only to hypericin, but to other constituents, including flavonoids.18 Isoquercetin is part of the flavonoids fraction of St. John’s wort that has been shown in animals to exhibit antidepressant activity, possibly by modulating HPA-axis regulation of ACTH and cortisol.19,20

Prevention of Diabetic Complications

Isoquercetin inhibits the formation of advanced glycation end-products (AGEs), one of primary pathologic mechanisms involved in diabetic complications and morbidity of aging.21 Treatment with quercetin significantly attenuated renal dysfunction and oxidative stress in diabetic rats as well as the neuropathic pain that accompanies the disease.22,23

Anti-inflammatory Effects

Quercetin is clinically used in the treatment of chronic prostatitis and related inflammatory conditions. In one study, quercetin supplementation provided significant symptomatic improvement in a majority of men with chronic pelvic pain syndrome.24 Quercetin therapy (500 mg twice daily for 4 weeks) also demonstrated significant symptomatic improvement in patients with interstitial cystitis and chronic pelvic pain syndrome in another study.25
Quercetin and quercetin glycosides have demonstrated beneficial effects in animal models of inflammation. Isoquercetin demonstrated slightly better anti-inflammatory efficacy than quercetin on the expression of COX-2 mRNA and inflammatory cell exudation, though overall effects of the two were roughly comparable in this in vitro study.26 
Quercetin and rutin inhibit the generation of inflammatory mediators (leukotriene LTB4 and prostaglandin E2) in human neutrophils.27 These flavonoids may therefore find application in the treatment of inflammatory conditions associated with excessive leukotriene production, such as rheumatoid arthritis and inflammatory bowel disease.28
Quercetin has been shown to inhibit cytokine and inducible nitric oxide synthase expression through inhibition of the NF-kappaB pathway, which further accounts for its anti-inflammatory capacity.29 Quercetin may also exert anti-inflammatory via systemic inhibition 
of TNF-a.30


Quercetin has been shown to stabilize mast cells against degranulation, resulting in a decrease in histamine release.31 In addition, anti-inflammatory actions, such as inhibition of neutrophil lysosomal enzyme secretion and leukotriene production,32,33 has led to the use of quercetin as a leading nutritional intervention for perennial allergic rhinitis.34

Absorption and Bioavailability

Absorption and bioavailability studies of quercetin and its glucosides have been conducted primarily in animals, such as rats and pigs.35,36,37,38,39 A few researchers have investigated the absorption and bioavailability of flavonoids in humans.40

Bioavailability Studies in Humans

Comparative pharmacokinetics in humans demonstrates that the absorption of quercetin, isoquercetin, and rutin in humans involves different mechanisms. Rutin has the lowest relative bioavailability and is not significantly absorbed before 2 hours, showing peak plasma concentrations at 6 hours after intake. Metabolites of isoquercetin appear within 30 minutes in the systemic circulation; a rapid rise to a peak at 30 minutes is seen with isoquercetin, suggesting active or enhanced transport; quercetin aglycone exhibits a slow rise to a plateau at 1–4 hours, indicating absorption by passive diffusion from the stomach and through the intestines.41,42
Hollman and colleagues in the Netherlands assessed the relative bioavailability and absorption of flavonoids from onions (glucose-conjugated quercetin), apples (both glucose conjugates and non-glucose conjugates), or pure quercetin-3-rutinoside in humans.43 
They found that absorption and bioavailability were highest for the quercetin glucosides, such as isoquercetin, lower for quercetin aglycone, and lowest for non-glucose quercetin glycosides such as rutin. 
No published study has directly compared the relative bioavailability of isolates of isoquercetin, quercetin aglycone, and rutin in humans, though some animal studies have. The presence of the glucoside moiety, whether in the 3´ or 4´ position, appears to be responsible for the increased bioavailability of isoquercetin and other quercetin glucosides, as compared with quercetin aglycone. Isoquercetin (quercetin-3-glucoside) has been shown to have bioavailability comparable to that of quercetin-4´-glucoside.44 The similarities are such that researchers often refer to the two glucosides interchangeably.45
In one study, men with ileostomies consumed a supplement of fried onions (which is rich in quercetin glucosides), pure rutin, or pure quercetin aglycone. The absorption of the flavonoids, defined as oral intake minus ileostomy excretion, was 52% for quercetin glucosides, 24% for quercetin, and 17% for rutin.46 Further investigations in which test subjects were fed pure quercetin-4´-glucoside or pure rutin showed similar results.47 The peak concentration of quercetin equivalents in plasma was 20 times higher and was reached more than 10 times faster after intake of quercetin glucoside (i.e., isoquercetin) compared to rutin. The authors proposed an active transport of the quercetin glucoside with the glucose transporter SGLT1 in the small intestine. In contrast, rutin is thought to be absorbed after deglycosylation in the colon.48,49 Although not all studies corroborate these results, the preponderance of evidence supports the superior bioavailability of quercetin glucosides compared to quercetin.50,51
The influence of plant matrix and sugar moiety of the glycoside on the absorption of flavonoids has been suggested as an important factor for the absorption of quercetin aglycone, but direct study of the influence of the plant matrix found no significant difference in the bioavailability and pharmacokinetic parameters between an onion supplement (containing mainly quercetin-4´-glucoside) and pure quercetin-4´-glucoside.52,53

Bioavailability Studies in Animals

Some bioavailability studies of quercetin have been performed in pigs since the anatomy and physiology of porcine and human digestive gastrointestinal tracts are similar. These studies are of particular interest because they directly compare the bioavailability of isoquercetin, quercetin aglycone, and rutin. Bioavailability is highest for isoquercetin, lower for quercetin aglycone, and lowest for rutin. After intravenous and oral application in pigs, the bioavailability of oral quercetin was just 17%, compared with intravenously administered quercetin at 100%.54 In a similar study, the relative total bioavailability was 148% for isoquercetin. For Q3G and rutin, the relative total bioavailability of quercetin (i.e., conjugated quercetin and conjugated methylethers of quercetin) was 148% and 23% respectively, compared with quercetin aglycone.55 One study suggested dietary fat content may influence absorption of quercetin derivatives. Pigs were given 3%, 17%, or 32% fat in their diets as well as either isoquercetin or quercetin aglycone. The 17% fat diet has significantly increased absorption compared to the 3% diet, while the 32% diet did not increase the absorption further. 
Isoquercetin, which is less lipophilic than quercetin aglycone, showed better bioavailability regardless of percentage of fat consumed.56 Direct comparisons of the bioavailability of isoquercetin, quercetin aglycone, and rutin have also been made in rats. As with pigs, bioavailability in the small intestine was highest for isoquercetin, lower for quercetin aglycone, and lowest for rutin.57 Rats given quercetin, isoquercetin, rutin or quercetin-3-rhamnoside achieved plasma concentration 2.5 to 3 times higher with isoquercetin compared to quercetin aglycone.58,59

Mechanisms of Absorption

Quercetin and isoquercetin (and other glucosides like quercetin-4´-glucoside) are primarily absorbed by brush border enterocytes of the small intestine. Quercetin glycosides with sugar moieties other than glucose (e.g., rutinosides) are absorbed in lower parts of the intestinal tract after deglycosylation.
Quercetin glucosides are transported into the epithelial cells via sodium-dependent glucose transporter (SGLT1).60 Luminal hydrolysis of the quercetin glucoside is by the lactase phlorizin hydrolase (LPH) enzyme.61 LPH is an extracellular ß-glycosidase located on the brush border membrane of intestinal cells. LPH is the only mammalian glucosidase that is present on the luminal side of the brush border, so it can act on dietary glycosides in the lumen, before absorption. Quercetin glucosides are deglycosylated by LPH. The resulting aglycone then enters epithelial cells by passive diffusion. This process is possibly enhanced by the proximity to the cellular membrane.62,63 


After ingestion of isoquercetin, quercetin, and rutin, quercetin aglycone and intact glycosides of quercetin are not detectable in human plasma and body tissues in significant amounts as these parent compounds. Instead, quercetin occurs principally as glucuronated, sulfated, and methylated quercetin conjugates. This has been demonstrated in humans as well as in animals.64,65,66 Day and colleagues identified quercetin-3´-O-glucuronide, 3´-O-methylquercetin-3-O-glucuronide, and quercetin-3´-O-sulfate as the major conjugates.67 Approximately 20–40% of quercetin is methylated in the 3´-position, yielding isorhamnetin.68,69
In humans, about 93% of quercetin is metabolized in the gut.70 Quercetin diglucuronides and glucuronyl sulfates of methylated quercetin in plasma are the major metabolites, and data suggest that the in vivo bioactivity of quercetin is due to these metabolites. Research on the neuroactivity of St. John’s wort suggests that some of these quercetin metabolites can cross the blood-brain barrier.71,72

Why not just eat more onions?

It remains controversial whether or not the food matrix confers advantages in terms of bioavailability of quercetin and its glycosides. As has been demonstrated for other nutrients (e.g., lutein for macular degeneration), epidemiological evidence of a beneficial effect of a particular nutrient does not always translate into a beneficial effect of the isolated nutrient. This leads some nutritionally oriented doctors to shun isolated nutrients in favor of obtaining the nutrients from foods.
This is complicated by the findings that some therapeutic quantities of a desired nutrient are not practical to obtain from the diet. Further, food preparation may degrade their bioactivity. In the case of quercetin derivatives, onions are a major source of quercetin glucosides. However, roasting onions for over 60 minutes at 180°C degrades onion quercetin glucosides.73 Most people prefer not to eat onion raw, at least in large quantities. Moreover, levels of quercetin glucosides vary considerably from one type of onion to another (e.g., they nearly absent from white onions).74 Quercetin glucoside levels also decrease significantly as onions age.75 According to Graefe and colleagues in  their definitive study of the pharmacokinetics and bioavailability of quercetin glycosides in humans, “The plant matrix of onions has no determinable impact on the absorption of quercetin glucosides.”76


There are no cases of adverse events from isoquercetin supplementation in the literature. It has been reported that quercetin (aglycone) supplementation can cause elevations of plasma homovanillic acid.77 Early in vitro research suggested that quercetin aglycone could be a potential mutagen.78,79,80,81,82,83,84,85,86,87 Although more definitive in vivo studies found no mutagenicity and quercetin has been found to be free of reproductive toxicity and developmental toxicity, it is nevertheless prudent that pregnant women not use quercetin supplements, including isoquercetin.88,89,90,91,92,93,94,95 
Quercetin supplements, including isoquercetin, should also be avoided by people taking cyclosporine, estradiol, nifedipine, or felodipine. In an animal study, oral administration of quercetin (50 mg/kg BW) at the same time as cyclosporine decreased the absorption of cyclosporine by 43%.96 In another study, however, supplementing with quercetin along with cyclosporine significantly increased blood levels of cyclosporine, compared to cyclosporine alone.97 Naringenin, quercetin, and kaempferol, all present in grapefruit, are inhibitors of cytochrome P-450 metabolism. All of these flavonoids can inhibit metabolism of 17 beta-estradiol.98 Therefore, people on estrogen replacement therapy should consult with their physician before taking quercetin or any concentrated flavonoid-containing product. Quercetin has also inhibited the metabolism of nifedipine and felodipine by cytochrome P-450 3A4.99 There are no reports in the medical literature of drug interactions with isoquercetin.


A conservative estimate puts the relative bioavailability of isoquercetin at 3–5 times that of quercetin aglycone. Thus it is anticipated that a lower does of isoquercetin would be required for comparable efficacy. As a rule of thumb, isoquercetin could be supplemented in a ratio of 1:5 relative to quercetin aglycone. Thus, for example, in revising a regimen in which 500 mg per day of quercetin aglycone is being given, the physician would recommend an isoquercetin supplement of 100 mg per day.

About the Author

Jeremy Appleton, ND, is a licensed naturopathic physician. He is a graduate of Reed College and the National College of Natural Medicine. He served on faculty at NCNM as the nutrition department chair and has also taught at Bastyr University, where he did his residency. Appleton left his private practice in 1998 to work in the natural products industry. He is the author of several books and hundreds of articles on natural medicine. He currently serves as director of scientific affairs at Integrative Therapeutics.


  1. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J Nutr. 2007;137(11):2405-2411.
  2. Chopra M, Fitzsimons PE, Strain JJ, et al. Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations. Clin Chem. 2000;46(8 Pt 1):1162-1170.
  3. Conquer JA, Maiani G, Azzini E, Raguzzini A, Holub BJ. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J Nutr.1998;128(3):593-597.
  4. Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J Thromb Haemost. 2004;2(12):2138-2145.
  5. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD.Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr. 2008;88(4):1018-1025.
  6. Vitor RF, Mota-Filipe H, Teixeira G et al. Flavonoids of an extract of Pterospartum tridentatum showing endothelial protection against oxidative injury. J Ethnopharmacol. 2004;93(2-3):363-370.
  7. Nees S, Weiss DR, Reichenbach-Klinke E, et al. Protective effects of flavonoids contained in the red vine leaf on venular endothelium against the attack of activated blood components in vitro. Arzneimittelforschung. 2003;53(5):330-341.
  8. Reiter RJ. Oxidative processes and antioxidative defense mechanism in the aging brain, FASEB J 1995;9:526-533.
  9. Dajas F, Rivera-Megret F, Blasina F, et al. Neuroprotection by flavonoids. Braz J Med Biol Res. 2003 36(12):1613-1620.
  10. Dok-Go H, Lee KH, Kim HJ. Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res. 2003;965(1-2):130-136.
  11. Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem. 2004;52(25):7514-7517.
  12. Takizawa S, Fukuyama N, Hirabayashi H, et al. Quercetin, a natural flavonoid, attenuates vacuolar formation in the optic tract in rat chronic cerebral hypoperfusion model. Brain Res. 2003;980(1):156-160.
  13. Krasteva I, Nikolova I, Danchev N, Nikolov S. Phytochemical analysis of ethyl acetate extract from Astragalus corniculatus Bieb. and brain antihypoxic activity. Acta Pharm. 2004;54:151-156.
  14. Singh A, Naidu PS, Kulkarni SK. Reversal of aging and chronic ethanol-induced cognitive dysfunction by quercetin a bioflavonoid. Free Radical Research. 2003;37:1245-1252.
  15. Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. Pharmacology. 2003;69(2):59-67.
  16. Naidu PS, Singh A, Kulkarni SK. Reversal of reserpine-induced orofacial dyskinesia and cognitive dysfunction by quercetin. Pharmacology. 2004;70(2):59-67.
  17. Chang Q, Zuo Z, Chow MS, Ho WK. Difference in absorption of the two structurally similar flavonoid glycosides, hyperoside and isoquercitrin, in rats. Eur J Pharm Biopharm. 2005;59(3):549-555.
  18. Caccia S. Antidepressant-Like Components of Hypericum perforatum Extracts: An Overview of Their Pharmacokinetics and Metabolism. Current Drug Metabolism. 2005;6:531-533.
  19. Butterweck V, Jurgenliemk G, Nahrstedt A, Winterhoff H. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test. Planta Med. 2000;66(1):3.
  20. Butterweck V, Hegger M, Winterhoff H . Flavonoids of St. John’s Wort reduce HPA axis function in the rat. Planta Med. 2004;70(10):1008-1011.
  21. Kim HY, Moon BH, Lee HJ, Choi DH. Flavonoid glycosides from the leaves of Eucommia ulmoides O. with glycation inhibitory activity. J Ethnopharmacol. 2004;93(2-3):227-230.
  22. Anjaneyulu M, Chopra K. Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 2004;31(4):244-248.
  23. Anjaneyulu M, Chopra K, Kaur I. Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-induced diabetic mice. J Med Food. 2003;6;4:391-395.
  24. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J.Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology. 1999;54(6):960-963.
  25. Katske F, Shoskes DA, Sender M, et al. Treatment of interstitial cystitis with a quercetin supplement. Tech Urol. 2001;7(1):44-46.
  26. Morikawa K, Nonaka M, Narahara M, et al. Inhibitory effect of quercetin on carrageenan-induced inflammation in rats. Life Sci. 2003;74(6):709-721.
  27. Bouriche H, Miles FA, Selloum L, Calder PC. Effect of Cleome arabica leaf extract, rutin and quercetin on soybean lipoxygenase activity and on generation of inflammatory eicosanoids by human neutrophils. Prostaglandins Leukot Essent Fatty Acids. 2005;72:195-201.
  28. Crofford LJ, Lipsky PE, Brooks P, Abrahamson SB, Simon LS, Van de Putte LB. Basic biology and clinical application of specific cycloxygenase-2 inhibitors. Arthritis Rheum. 2000;43:4-13.
  29. Comalada M, Camuesco D, Sierra S, et al. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol. 2005;35(2):584-592.
  30. Ueda H, Yamazaki C, Yamazaki M. A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor-alpha production. Biosci Biotechnol Biochem 2004;68(1):119-125.
  31. Otsuka H, Inaba M, Fujikura T, Kunitomo M. Histochemical and functional characteristics of metachromic cells in the nasal epithelium in allergic rhinitis: studies of nasal scrapings and their dispersed cells. J Allergy Clin Immunol. 1995;96:528-536.
  32. Busse WW, Kopp DE, Middleton E. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol. 1984;73:801-809.
  33. Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer . Pharmacol Rev. 2000;52(4):673-751.
  34. Thornhill SM, Kelly AM. Natural treatment of perennial allergic rhinitis. Altern Med Rev. 2000;5(5):448-454.
  35. Morand C, Manach C, Crespy V, Remesy C. Quercetin 3-O-b-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Rad Res. 2000;33(5):667-676.
  36. Morand C, Manach C, Crespy V, Remesy C. Respective bioavailability of quercetin aglycone and its glycosides in a rat model. Biofactors. 2000;12(1-4):169-174.
  37. Ader P, Wessmann A, Wolffram S. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic Biol Med. 2000;28(7):1056-1067.
  38. Lesser S, Cermak R, Wolffram S. Bioavailability of quercetin in pigs is influenced by the dietary fat content. J Nutr. 2004;134(6):1508-1511.
  39. ermak R, Landgraf S, Wolffram S. The bioavailability of quercetin in pigs depends on the glycoside moiety and on dietary factors. J Nut. 2003;133(9):2802-2807.
  40. Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr. 2005;81(1 Suppl):243S-255S.
  41. Olthof MR, Hollman PCH, Vree B, Katan MB. Bioavailabilities of quercetin-3-glucoside and quercetin-4’-glucoside do not differ in humans. J Nutr. 2000;130(5):1200-1203.
  42. Erlund I, Kosonen T, Alfthan G, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Pharmacol. 2000;56:545-554.
  43. Hollman PCH, van Trijp JMP, Busyman MNCP, et al. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Letters. 1997;418:152-156.
  44. Olthof MR, Hollman PCH, Vree B, Katan MB. Bioavailabilities of quercetin-3-glucoside and quercetin-4’-glucoside do not differ in humans. J Nutr. 2000;130(5):1200-1203.
  45. Murota K, Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch Biochem Biophys. 2003;417(1):12-17.
  46. Hollman PCH, van Trijp JMP, Mengelers MJB, de Vries JHM, Katan MB. Bioavailability of the dietary antioxidant flavonol quercetin in man. Cancer Lett. 1997;14:139-140.
  47. Hollman PC, Bijsman MN, van Gameren Y, et al. The sugar moiety is a major determinant of the absorption of dietary flavonoid glucosides in man. Free Radic Res. 1999;31(6):569-573.
  48. Day AJ, DuPont MS, Ridley S, et al. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity. FEBS Lett. 1998;436(1):71-75.
  49. Nemeth K, Plumb GW, Berrin JG, et al. Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr. 2003;42(1):29-42.
  50. Walle T, Browning AM, Steed LL, et al. Flavonoid glycosides are hydrolyzed and thus activated in the oral cavity in humans. J Nutr. 2005;135(1):48-52.
  51. Wiczkowski W, Romaszko J, Bucinski A, et al. Quercetin from shallots(Allium cepa L. var. aggregatum) is more bioavailable than its glucosides. J Nutr. 2008;138(5):885-888.
  52. Wiczkowski W, Romaszko J, Bucinski A, et al. Quercetin from shallots (Allium cepa L. var. aggregatum) is more bioavailable than its glucosides. J Nutr. 2008;138(5):885-888.
  53. Graefe EU, Wittig J, Mueller S, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol. 2001;41(5):492-499.
  54. Ader P, Wessmann A, Wolffram S. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic Biol Med. 2000;28(7):1056-1067.
  55. Cermak R, Landgraf S, Wolffram S. The bioavailability of quercetin in pigs depends on the glycoside moiety and on dietary factors. J Nut. 2003;133(9):2802-2807.
  56. Lesser S, Cermak R, Wolffram S. Bioavailability of quercetin in pigs is influenced by the dietary fat content. J Nutr. 2004;134(6):1508-1511.
  57. Manach C, Morand C, Demigné C, Texier O, Régérat F, Rémésy C. Bioavailability of rutin and quercetin in rats. FEBS Lett. 1997;409(1):12-16. 
  58. Morand C, Manach C, Crespy V, Remesy C. Quercetin 3-O-b-glucoside is better absorbed than other quercetin forms and is not present in rat plasma.Free Rad Res. 2000;33(5):667-676.
  59. Morand C, Manach C, Crespy V, Remesy C. Respective bioavailability of quercetin aglycone and its glycosides in a rat model. Biofactors. 2000;12(1-4):169-174.
  60. Gee JM, DuPont MS, Day AJ, Plumb GW, Williamson G, Johnson IT. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr. 2000;130(11):2765-2771.
  61. Day AJ, Canada FJ, Diaz JC, et al. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Letters. 2000;468:166-170.
  62. Day AJ, Canada FJ, Diaz JC, et al. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Letters. 2000;468:166-170.
  63. Sesink ALA, Arts ICW, Faasen-Peters M, Hollman P. Intestinal uptake of quercetin-3-glucoside in rats involves hydrolysis by lactase phlorizin hydrolase. J Nutr. 2003;133:773-776.
  64. Sesink AL, O’Leary KA, Hollman PC. Quercetin glucuronides but not glucosides are present in human plasma after consumption of quercetin-3-glucoside or quercetin-4’-glucoside. J Nutr. 2001;131(7):1938-1941.
  65. Wittig J, Herderich M, Graefe EU, Veit M. Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001;753(2):237-243.
  66. Lesser S, Cermak R, Wolffram S. Bioavailability of quercetin in pigs is influenced by the dietary fat content. J Nutr. 2004;134(6):1508-1511.
  67. Day AJ, Mellon F, Barron D, et al. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radic Res. 2001;35(6):941-952.
  68. Olthof MR, Hollman PCH, Vree B, Katan MB. Bioavailabilities of quercetin-3-glucoside and quercetin-4’-glucoside do not differ in humans. J Nutr. 2000;130(5):1200-1203.
  69. Graefe EU, Wittig J, Mueller S, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol. 2001;41(5):492-499.
  70. Chen J, Lin H, Hu M. Metabolism of flavonoids via enteric recycling: role of intestinal disposition. J Pharmacol Experiment Ther. 2003;304(3):1228-1235.
  71. Graf BA, Mullen W, Caldwell ST. Disposition and metabolism of [2-14C] quercetin-4’-glucoside in rats. Drug Metab Dispos 2005;33(7):1036-1043.
  72. Paulke A, Schubert-Zsilavecz M, Wurglics M. Determination of St. John’s wort flavonoid-metabolites in rat brain through high performance liquid chromatography coupled with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;832(1):109-113. 
  73. Rohn S, Buchner N, Driemel G, Rauser M, Kroh LW. Thermal degradation of onion quercetin glucosides under roasting conditions. J Agric Food Chem. 2007;55(4):1568-1573. 
  74. Caridi D, Trenerry C, Rochfort S, Duong S, Laugher D, Jones R. Profiling and quantifying quercetin glucosides in onion (Allium cepa L.) varieties using capillary zone electrophoresis and high performance liquid chromatography. Food Chem. 2007;105:691-699.
  75. Takahama U, Hirota S. Deglucosidation of quercetin glucosides to the aglycone and formation of antifungal agents by peroxidase-dependent oxidation of quercetin on browning of onion scales. Plant Cell Physiol.2000;41(9):1021-1029.
  76. Graefe EU, Wittig J, Mueller S, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol. 2001;41(5):492-499.
  77. Weldin J, Jack R, Dugaw K, Kapur RP. Quercetin, an over-the-counter supplement, causes neuroblastoma-like elevation of plasma homovanillic acid. Pediatr Dev Pathol. 2003;6(6):547-551.
  78. Bjeldanes LF, Chang GW. Mutagenic activity of quercetin and related compounds. Science. 1977;197(4303):577-578.
  79. MacGregor JT, Jurd L. Mutagenicity of plant flavonoids: structural requirements for mutagenic activity in Salmonella typhimurium. Mutat Res. 1978;54(3):297-309.
  80. Brown JP, Dietrich PS. Mutagenicity of plant flavonols in the Salmonella/mammalian microsome test: activation of flavonol glycosides by mixed glycosidases from rat cecal bacteria and other sources. Mutat Res. 1979;66(3):223-240.
  81. Rueff J, Laires A, Borba H, Chaveca T, Gomes MI, Halpern M. Genetic toxicology of flavonoids: the role of metabolic conditions in the induction of reverse mutation, SOS functions and sister-chromatid exchanges. Mutagenesis. 1986;1(3):179-183.
  82. Carver JH, Carrano AV, MacGregor JT. Genetic effects of the flavonols quercetin, kaempferol, and galangin on Chinese hamster ovary cells in vitro. Mutat Res. 1983;113(1):45-60.
  83. Meltz ML, MacGregor JT. Activity of the plant flavanol quercetin in the mouse lymphoma L5178Y TK+/- mutation, DNA single-strand break, and Balb/c 3T3 chemical transformation assays. Mutat Res. 1981;88(3):317-324.
  84. Nakayasu M, Sakamoto H, Terada M, Nagao M, Sugimura T. Mutagenicity of quercetin in Chinese hamster lung cells in culture. Mutat Res.1986;174(1):79-83.
  85. van der Hoeven JC, Bruggeman IM, Debets FM. Genotoxicity of quercetin in cultured mammalian cells. Mutat Res. 1984;136(1):9-21.
  86. Maruta A, Enaka K, Umeda M. Mutagenicity of quercetin and kaempferol on cultured mammalian cells. Gann. 1979;70(3):273-276.
  87. Popp R, Schimmer O. Induction of sister-chromatid exchanges (SCE), polyploidy, and micronuclei by plant flavonoids in human lymphocyte cultures. A comparative study of 19 flavonoids. Mutat Res. 1991;246(1):205-213.
  88. MacGregor JT, Wehr CM, Manners GD, Jurd L, Minkler JL, Carrano AV. In vivo exposure to plant flavonols. Influence on frequencies of micronuclei in mouse erythrocytes and sister-chromatid exchange in rabbit lymphocytes. Mutat Res. 1983;124(3-4):255-270.
  89. Aeschbacher HU, Meier H, Ruch E. Nonmutagenicity in vivo of the food flavonol quercetin. Nutr Cancer. 1982;4(2):90-98.
  90. Caria H, Chaveca T, Laires A, Rueff J. Genotoxicity of quercetin in the micronucleus assay in mouse bone marrow erythrocytes, human lymphocytes, V79 cell line and identification of kinetochore-containing (CREST staining) micronuclei in human lymphocytes. Mutat Res. 1995;343(2-3):85-94.
  91. Ngomuo AJ, Jones RS. Genotoxicity studies of quercetin and shikimate in vivo in the bone marrow of mice and gastric mucosal cells of rats. Vet Hum Toxicol. 1996;38(3):176-180.
  92. Sahu RK, Basu R, Sharma A. Genetic toxicological of some plant flavonoids by the micronucleus test. Mutat Res. 1981;89(1):69-74.
  93. Willhite CC. Teratogenic potential of quercetin in the rat. Food Chem Toxicol. 1982;20(1):75-79.
  94. Rastogi PB, Levin RE. Induction of sperm abnormalities in mice by quercetin. Environ Mutagen. 1987;9(1):79-86.
  95. Aravindakshan M, Chauhan PS, Sundaram K. Studies on germinal effects of quercetin, a naturally occurring flavonoid. Mutat Res. 1985;144(2):99-106.
  96. Hsiu SL, Hou YC, Wang YH, et al. Quercetin significantly decreased cyclosporine oral bioavailability in pigs and rats. Life Sci. 2002;72:227-235.
  97. Choi JS, Choi BC, Choi KE. Effect of quercetin on the pharmacokinetics of oral cyclosporine. Am J Health Syst Pharm. 2004;61:2406-2409.
  98. Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet. 1995;20(3):219-224.
  99. Miniscalco A, Lundahl J, Regårdh CG, Edgar B, Eriksson UG. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J Pharmacol Exp Ther. 1992;261(3):1195-1199.