Combination Effects of Quercetin, Resveratrol and Curcumin on In Vitro Intestinal Absorption
Kaleb C Lund
Traci Pantuso


Intestinal absorption


Objective: Quercetin, resveratrol and curcumin are plant derived natural products that are rapidly gaining popularity as supplements for a wide assortment of conditions including cardiovascular disease, cancer, asthma, diabetes, neurodegeneration, aging and stress. Unfortunately the therapeutic potential of these compounds is limited by their poor intestinal and intracellular bioavailability. Therefore this study sought to examine how combinations of quercetin, resveratrol, and curcumin, with and without piperine, 200 nM, affected an in vitro permeability model using apical-to-basal permeability across intact caco-2 monolayers. Quercetin, resveratrol and curcumin were applied apically alone or in combination at 50 μM and measured in the basal chamber at 30 min.

Results: Resveratrol received the greatest enhancement in permeability when combined with other agents: quercetin (310%), curcumin (300%), quercetin and curcumin (323%, 350% with piperine). Curcumin also demonstrated increased permeability when combined with quercetin alone (147%) and both quercetin and resveratrol (188%), addition of piperine resulted in a 229% increase in permeability. Quercetin permeability was not significantly affected using any combination, but showed maximal permeability when combined with resveratrol and the lowest permeability when combined with resveratrol, curcumin and piperine together.

Conclusion: Combination of quercetin, resveratrol and curcumin may improve intestinal absorption of resveratrol and curcumin without affecting quercetin absorption. These data highlight the need for further research and suggest that developing combination therapies may improve intestinal absorption of these constituents. Our study also demonstrates that the apical-to-basal permeability across intact caco-2 monolayer model is a viable model to investigate absorption of natural compounds.



Boots AW, Haenen GRMM, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008; 585(2–3):325–37.
Dajas F. Life or death: neuroprotective and anticancer effects of quercetin. J Ethnopharmacol. 2012; 143(2):383–96.
Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol. 2012; 83(1):6–15.
Prasad K. Resveratrol, wine, and atherosclerosis. Int J Angiol. 2012; 21(1):7–18.
Raederstorff D, Kunz I, Schwager J. Resveratrol, from experimental data to nutritional evidence: the ememrgence of a new food ingredient. Ann NY Acad Sci. 2013; 1290:136–41.
Xu Q, Si L-Y. Resveratrol role in cardiovascular and metabolic health and potential mechanisms of action. Nutr Res. 2012; 32(9):648–58.
Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009; 41(1):40–59.
Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis.Phytother Res. 2012; 26(11):1719–25.
DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people.Nutr J. 2012; 11(1):79–87.
Lao CD, Mack I, Ruffin T, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006; 6(10):1–4. doi:10.1186/1472-6882-6-10 .
Porte CL, Voduc N, Zhang G, Seguin I, Tardiff D, Singhal N, Cameron DW. Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet. 2010; 49(7):449–54.
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998; 64(4):353–6.
Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011; 74(4):664–9.
Atal CK, Dubey RK, Singh J. Biochemical basis of enhance drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther. 1985; 232(1):258–62.
Zhou S, Lim LY, Chobay B. Herbal modulation of P-glycoprotein. Drug Metab Rev. 2004; 36(1):57–104.
Okura T, Ibe M, Umegaki K, Shinozuka K, Yamada S. Effects of dietary ingredients on function and expression of P-glycoprotein in human intestinal epithelial cells. Biol Pharm Bull. 2010; 33(2):255–9.
Li Y, Shin YG, Yu C, Kosmeder JW, Hirschelman WH, Pezzuto JM, Breemen RBV. Increasing the throughput and productivity of Caco-2 cell permeability assays using liquic chromatography-mass spectrometry: application to resveratrol absorption and metabolism. Comb Chem High Throughput Screen. 2003; 6:757–67.
Wahlang B, Pawar YB, Bansal AK. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm. 2011; 77:275–82.
Center for Drug Evaluation and Research. Guidance for Industry: Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate-release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Rockville, MD: Food and Drug Administration; 2000.
Zhang L, Lin G, Kovacs B, Jani M, Krajcsi P, Zuo Z. Mechanistic study on the intestinal absorption and disposition of baicalein. Eur J Pharm Sci. 2007; 31:221–31.
Zhang L, Zheng Y, Chow MSS, Zuo Z. Investigation of intestinal absorption and disposition of green tea catechins by Caco-2 monlayer model.Int J Pharm. 2004; 287:1–12.
Olson ER, Melton T, Dong Z, Bowden GT. Stabilization of quercetin paradoxically reduces its proapoptotic effect on UVB-irradiated human keratinocytes. Cancer Prevent Res. 2008; 1(5):362–8.
De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulfation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Xenobiotica. 2000; 30(6):609–17.
De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids. Xenobiotica. 2000; 30(9):857–66.
Choi JS, Piao YJ, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin.Arch Pharm Res. 2011; 34(4):607–13.
Sergent T, Dupont I, Van der Heiden E, Scippo ML, Pussemier L, Larondelle Y, Scheider YJ. CYP1A1 and CYP3A4 modulation by dietary flavonoids in human intestinal Caco-2 cells. Toxicol Lett. 2009; 191(2–3):216–22.
De Santi C, Pietrabissa A, Mosca F, Rane A, Pacifici GM. Inhibition of phenol sulfotransferase (SULT1A1) by quercetin in human adult and foetal livers. Xenobiotica. 2002; 32(5):363–8.
Marchetti F, De Santi C, Vietri M, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Differential inhibition of human liver and duodenum sulphotransferase activities by quercetin, a flavonoid present in vegetables, fruit and wine. Xenobiotica. 2001; 31(12):841–7.
Kim KA, Park PW, Park JY. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol. 2009; 65(6):609–14.
Bansal T, Awasthi A, Jaggi M, Khar RK, Talegaonkar S. Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible ocntribution of P-glycoprotein. Life Sci. 2008; 83:250–9.
Ampasavate C, Sotanaphun U, Phattanawasin P, Piyapolrungroj N. Effects of Curcuma spp. on P-glycoprotein function. Phytomedicine. 2010; 17:506–12.
Cho YA, Lee W, Choi JS. Effects of curcumin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats: possible role of CYP3A4 and P-glycoprotein inhibition by curcumin. Pharmazie. 2012; 67(2):124–30.
Planas JM, Alfaras I, Colom H, Juan ME. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters. Arch Biochem Biophys. 2012; 527(2):67–73.
van de Wetering K, Burkon A, Feddema W, Bot A, de Jonge H, Somoza V, Borst P. Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol. Mol Pharmacol. 2009; 75(4):876–85.
Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, Fukizawa S, Morimoto N, Ieiri I, Morishita M, Sumita K, Mayahara H, Fujita T, Maeda K, Sugiyama Y. Pharmacokinetic interaction study of sulfasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor or BCRP. Br J Pharmacol. 2012; 166(6):1793–803.
Li S, Lei Y, Jia Y, Li N, Wink M, Ma Y. Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells. Phytomedicine. 2011; 19(1):83–7.
Iwuchukwu OF, Tallarida RJ, Nagar S. Resveratrol in combination with other
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.