Bioavailability

Improving Flavonoid Absorption Through Glucose Conjugation

The subject of over 10,000 published studies and scholarly reviews to date, quercetin is the most extensively researched flavonoid. If there is a “perfect” dietary antioxidant, quercetin is the one—it meets all major structural criteria to effectively scavenge reactive oxygen species.  Its clinical utility extends far beyond this, with anti-inflammatory and mast cell stabilizing properties lending evidence-based value in atopic conditions [1,2].

By virtue of its ability to donate electrons, quercetin is one of the most powerful free radical scavengers in the human diet [1, 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].

Three problems

The structural features that make quercetin effective are the same features that limit bioavailability and disposition. The many hydroxyl groups decorating its ring system introduce 3 classical hindrances affecting many polyphenols:

  1. Low aqueous solubility, which limits dissolution in the intestine. Dissolution is a basic requirement for absorption.
  2. Dependence of passive diffusion to cross membranes, which is slow and incomplete.
  3. Phase II metabolism (sulfating and glucuronidation), which abolishes antioxidant activity and sends the flavonoid out of the body.

Solving for #1-3

Introducing a glucose moiety at the 3 and/or 4’ positions enhances solubility and uptake. Absorption of quercetin glucoside (isoquercetin) from 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.

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. *Quercetin is subject to inactivation by glucuronidation via UDP-glucuronosyltransferase (UGT), which is inhibited by piperine (Bioperine®).

A glucose functionality acts as a “homing device,” guiding it to glucose transporters in the intestinal wall, which actively pump the compound across membranes, instead of letting it linger and trickle across passively at its leisure.

Elegant lines of experimental inquiry have demonstrated that the glucose moiety, akin to a forged passport, exploits an active glucose transporter whose purpose is to drive dietary glucose across the intestinal wall [7]. This affords not only better absorption, but faster absorption. While peak levels of quercetin are reached within 2-4 hours, isoquercetin delivers peak concentrations in less than 40 minutes [8,9]. 

Such rapid entry into cells, where phase I and II enzymes reside, may theoretically saturate them, leading to a reduction in presystemic inactivation.

Structure of quecetin glucoside (isoquercetin). This sugar attachment may enhance the absorption of structurally related flavonoids.

Medicinal chemists need not apply

By design, this is not mankind’s work—flavonoid glycosylation is an everyday occurrence in plants.  Onion is one of the best sources of naturally occurring isoquercetin. The compound is also available as a dietary supplement.

Broader application

Quercetin analogs such as myricetin, luteolin and baicalein are good candidates for glycosidic conjugation as a safe and effective method of bioavailability enhancement. However, extension of this principle to other phytochemical classes is limited as glucose transporters may reject larger, more lipophilic substrates.

Other technologies

Piperine is an alkaloid from black pepper that inhibits glucuronidation of flavonoids and other compounds whose bioavailability is limited by phenolic hydroxyl groups (e.g. curcumin, resveratrol). In the mid-1990s, researchers reported that piperine increased the bioavailability of curcumin in both rats and humans [10]. More recently, piperine enhanced the pharmacokinetic parameters of resveratrol. It is now clear that piperine effectively targets and moderates UGT.  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].

Other technologies include liposomes, which improve dissolution and membrane permeation. However, liposomes are difficult to create. Quality assurance should include electron microscopy imaging to prove the presence of authentic liposomes.

Phytosomes have proven efficacy for curcumin, quercetin and similar phenolic compounds and are relatively simple to manufacture. These preparations are widely available and well-supported by published human clinical pharmacokinetic data.

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.

References

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