Enhancing quercetin bioavailability: A two-stage approach without excipients.

Article by Arnie Gitomer

The subject of over 10,000 published studies and scholarly reviews to date, quercetin is the most extensively researched flavonoid.  Its clinical applications are diverse, with cardiovascular, neurocognitive and immune health at the forefront of an expanding therapeutic profile.1  Initially acclaimed for its antioxidant activity, the past decade of research has underscored cellular signal transduction, enzyme activity and gene expression as major conduits of its health benefits.*
By virtue of its ability to donate electrons, this archetypal flavonoid is one of the most powerful free radical scavengers in the human diet.2  However, the structural attributes that afford this capability also impair diffusion across membranes.2 Accordingly, pharmacokinetic studies indicate that only 20-30% of an oral dose is absorbed.3,4  Despite its ephemeral presence in plasma, studies report clinically significant responses to oral quercetin supplementation.1 Toward the goal of maximizing efficacy, bioavailability optimization remains an ongoing focus of research and formulation.*
A suggestion from nature
Major dietary sources of quercetin include onions, apples and tea.2  In contrast to the form in most supplements, most of the quercetin in foods is attached to a sugar molecule.  This conjugate is known as a glycoside.  The onion plant tends to affix glucose to form quercetin-3-glucoside (isoquercetin), while apple trees and tea plants tend to attach rutinose, yielding rutin.2  Considering the size and polarity of these cumbersome structural accessories, some rules of medicinal chemistry would predict difficulty crossing membranes.  Antithetically, for isoquercetin, this is not the case.*  
Clinical research conducted in the Netherlands has compared quercetin bioavailability from different foods and supplements.4,5  Absorption from isoquercetin-rich onions was 52%, compared to 24% from a standard quercetin supplement.5  In parallel, animal studies have consistently documented superior bioavailability of isoquercetin relative to quercetin and rutin.6  Taken together, the studies show that isoquercetin is 2-6-fold more bioavailable than its alycone, quercetin.*
In vitro studies pursued a hypothesis that the glucose moiety, akin to a forged passport, was using a transporter that normally pumps glucose across membranes of the intestinal wall.  Elegant lines of experimental inquiry confirmed this biochemical exploitation as the mechanism of action.7  The rapid absorption observed with isoquercetin is consistent with this active transport.  For quercetin and rutin, which cannot use the transporter, peak levels are reached within 2-4 and 6-8 hours, respectively.8,9  Isoquercetin, in contrast, can deliver peak concentrations in less than 40 minutes.8*
Overcoming a second challenge
Regardless of the preparation, quercetin encounters an additional hurdle in the intestinal mucosa and liver.  The enzyme UDP-glucuronosyltransferase (UGT) conjugates free quercetin with glucuronide, a bulky and inert adduct, hindering its functional dexterity and cellular actions.  Since the conjugate is easily excreted, UGT also accelerates its systemic clearance, limiting exposure of the flavonoid to target tissues.2*
Quercetin is not alone in this tribulation, as UGT wields a notorious predilection for flavonoids and other polyphenols.  In the mid-1990s, researchers reported that piperine, an alkaloid from black pepper, increased the bioavailability of curcumin in both rats and humans.10  More recently, piperine enhanced the pharmacokinetic parameters of resveratrol.11  It is now clear that piperine effectively targets and moderates UGT.12  While more research is necessary to evaluate the effects of piperine on quercetin action in humans, preliminary evidence, published in July 2013, indicates that piperine can enhance the neurocognitive efficacy of quercetin in mice.13*
 
Figure 1.  Quercetin bioavailability is enhanced in two steps when isoquercetin and piperine (Bioperine®) are combined: First, isoquercetin, or glycosylated quercetin, is absorbed more efficiently than free quercetin due to its glucose moiety. During absorption, the glucose is released, liberating free quercetin into the bloodstream to access tissues. Second, plasma quercetin is subject to inactivation by the enzyme UDP-glucuronosyltransferase (UGT).  Piperine (Bioperine®) directly targets this enzyme to maximize the durability of quercetin in the body.*
Collectively, the evidence supports that isoquercetin offers rapid absorption and superior overall bioavailability.  Since the sugar moiety serves merely as a delivery vehicle, its therapeutic profile is identical to quercetin.  Modeled after nature's example, isoquercetin is an excipient-free approach to bioavailability enhancement.  Isoquercetin w/Bioperine® delivers isoquercetin in combination with longer-acting rutin, together with clinically researched Bioperine® piperine to maximize clinical efficacy.*
 
References
1. Bischoff SC. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care (2008) 11(6):733-740.  
2. Heim K, Tagliaferro AR, Bobilya DJ.  Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem (2002) 13(10):572-584.
3. Ueno I, Nakano N, Hirono I. Metabolic fate of [14C] quercetin in the ACI rat.  Jpn J Exp Med (1983) 53(1):41-50.
4. Hollman PC,  van Trijp JM, Mengelers MJ, et al. Bioavailability of the dietary antioxidant flavonol quercetin in man. Cancer Lett (1997) 114(1-2):139-140.
5. Hollman PC, van Trijp JM, Buysman MN, et al. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Lett (1997) 418(1-2):152-156.
6. Manach C, Morand C, Demigné C, et al. Bioavailability of rutin and quercetin in rats. FEBS Lett (1997) 409(1):12-16.
7. Gee JM, DuPont MS, Day AJ, et al. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr (2000) 130(11):2765-2771.
8. Olthof MR, Hollman PC, Vree TB, Katan MB. Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans. J Nutr (2000) 130(5):1200-1203.
9. Erlund I, Kosonen T, Alfthan G, et al.  Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol (2000) 56(8):545-553.
10. Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med (1998) 64(4):353-356.
11. Johnson JJ, Nihal M, Siddiqui IA, et al. Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res (2011) 55(8):1169-1176.
12. Srinivasan K. Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr (2007) 47(8):735-48.
13. Rinwa P, Kumar A. Quercetin along with piperine prevents cognitive dysfunction, oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress. Arch Pharm Res (2013) Jul 16. Advance Online Publication. DOI 10.1007/s12272-013-0205-4.

*These statements have not been evaluated by the Food & Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.