Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 3, pp 593–601 | Cite as

Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

  • Izet M. Kapetanovic
  • Miguel MuzzioEmail author
  • Zhihua Huang
  • Thomas N. Thompson
  • David L. McCormick
Original Article



Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4′-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats.


The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters.


Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites.


When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol.


Resveratrol Pterostilbene Pharmacokinetics Bioavailability Metabolites Rat 



Ethylenediaminetetraacetic acid


Quality control


Mobile phase


Lowest limit of quantitation


Time to maximum plasma concentration


Peak plasma concentration


Area under the curve


Elimination half-life




Apparent volume of distribution


Percent bioavailability



These studies were supported by contract number N01-CN-43304 from the National Cancer Institute, Department of Health and Human Services. The authors thank Leigh Ann Senoussi for assistance in preparing the manuscript.


  1. 1.
    Abd El-Mohsen M, Bayele H, Kuhnle G, Gibson G, Debnam E, Kaila Srai S, Rice-Evans C, Spencer JP (2006) Distribution of [3H]trans-resveratrol in rat tissues following oral administration. Br J Nutr 96:62–70PubMedCrossRefGoogle Scholar
  2. 2.
    Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009) Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 486:95–102PubMedCrossRefGoogle Scholar
  3. 3.
    Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL (2007) Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 224:274–283PubMedCrossRefGoogle Scholar
  4. 4.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506PubMedCrossRefGoogle Scholar
  5. 5.
    Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res 2:409–418CrossRefGoogle Scholar
  6. 6.
    Boocock DJ, Faust GES, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16:1246–1252PubMedCrossRefGoogle Scholar
  7. 7.
    Brisdelli F, D’Andrea G, Bozzi A (2009) Resveratrol: a natural polyphenol with multiple chemopreventive properties (Review). Curr Drug Metab 10:530–546PubMedGoogle Scholar
  8. 8.
    Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD, Vasilinin G, Sen A, Schinas A, Piccirilli G, Brown K, Steward W, Gescher AJ, Brenner DE (2010) Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics and effect on the insulin-like growth factor axis. Cancer Res [Epub ahead of print]Google Scholar
  9. 9.
    Calamini B, Ratia K, Malkowski MG, Cuendet M, Pezzuto JM, Santarsiero BD, Mesecar AD (2010) Pleiotropic mechanisms facilitated by resveratrol and its metabolites. Biochem J 429(2):273–282PubMedCrossRefGoogle Scholar
  10. 10.
    Chakraborty A, Gupta N, Ghosh K, Roy P (2010) In vitro evaluation of the cytotoxic, anti-proliferative and anti-oxidant properties of pterostilbene isolated from Pterocarpus marsupium. Toxicol Vitr 24:1215–1228Google Scholar
  11. 11.
    Das DK (2006) Resveratrol in cardioprotection: a therapeutic promise of alternative medicine. Mol Interv 6:36–47PubMedCrossRefGoogle Scholar
  12. 12.
    Das S, Lin HS, Ho PC, Ng KY (2008) The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 25:2593–2600PubMedCrossRefGoogle Scholar
  13. 13.
    De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM (2000) Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Xenobiotica 30:609–617PubMedCrossRefGoogle Scholar
  14. 14.
    Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME (2006) Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 90:5–22PubMedCrossRefGoogle Scholar
  15. 15.
    Goswami SK, Das DK (2009) Resveratrol and chemoprevention. Cancer Lett 284:1–6PubMedCrossRefGoogle Scholar
  16. 16.
    Hoshino J, Park EJ, Kondratyuk TP, Marler L, Pezzuto JM, van Breemen RB, Mo S, Li Y, Cushman M (2010) Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites. J Med Chem 53:5033–5043PubMedCrossRefGoogle Scholar
  17. 17.
    Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220PubMedCrossRefGoogle Scholar
  18. 18.
    Kraft TE, Parisotto D, Schempp C, Efferth T (2009) Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev Food Sci Nutr 49:782–799PubMedCrossRefGoogle Scholar
  19. 19.
    Kuhnle G, Spencer JP, Chowrimootoo G, Schroeter H, Debnam ES, Srai SK, Rice-Evans C, Hahn U (2000) Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Biochem Biophys Res Commun 272:212–217PubMedCrossRefGoogle Scholar
  20. 20.
    Kundu JK, Surh YJ (2008) Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett 269:243–261PubMedCrossRefGoogle Scholar
  21. 21.
    Langcake P (1981) Disease resistance of Vitis spp. and the production of the stress metabolites resveratrol, epsilon-viniferin, alpha-viniferin and pterostilbene. Physiol Plant Pathol 18:213–226Google Scholar
  22. 22.
    la Porte C, Voduc N, Zhang G, Seguin I, Tardiff D, Singhal N, Cameron DW (2010) Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet 49(7):449–454PubMedCrossRefGoogle Scholar
  23. 23.
    Lin H-S, Yue B-D, Ho PC (2009) Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre-clinical pharmacokinetic study. Biomed Chromatogr 23:1308–1315PubMedCrossRefGoogle Scholar
  24. 24.
    Mannal PW, Alosi JA, Schneider JG, McDonald DE, McFadden DW (2010) Pterostilbene inhibits pancreatic cancer in vitro. J Gastrointest Surg 14:873–879Google Scholar
  25. 25.
    Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP (2002) Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther 302:369–373PubMedCrossRefGoogle Scholar
  26. 26.
    Marques FZ, Markus MA, Morris BJ (2009) Resveratrol: cellular actions of a potent natural chemical that confers a diversity of health benefits. Int J Biochem Cell Biol 41:2125–2128PubMedCrossRefGoogle Scholar
  27. 27.
    Pan Z, Agarwal AK, Xu T, Feng Q, Baerson SR, Duke SO, Rimando AM (2008) Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol. BMC Med Genomics 1:7PubMedCrossRefGoogle Scholar
  28. 28.
    Paul S, DeCastro A, Lee HJ, Smolarek AK, So JY, Simi B, Wang CX, Zhou R, Rimando AM, Suh N (2010) Dietary intake of pterostilbene, a constituent of blueberries, inhibits the {beta}-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats. Carcinogenesis 31:1272–1278PubMedCrossRefGoogle Scholar
  29. 29.
    Paul S, Rimando AM, Lee HJ, Ji Y, Reddy BS, Suh N (2009) Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells. Cancer Prev Res 2:650–657CrossRefGoogle Scholar
  30. 30.
    Pervaiz S, Holme AL (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11:2851–2897PubMedCrossRefGoogle Scholar
  31. 31.
    Pezzuto JM (2008) Resveratrol as an inhibitor of carcinogenesis. Pharm Biol 46:443–573CrossRefGoogle Scholar
  32. 32.
    Pirola L, Frojdo S (2008) Resveratrol: one molecule, many targets. IUBMB Life 60:323–332PubMedCrossRefGoogle Scholar
  33. 33.
    Rimando AM, Cuendet M, Desmarchelier C, Mehta RG, Pezzuto JM, Duke SO (2002) Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. J Agric Food Chem 50:3453–3457PubMedCrossRefGoogle Scholar
  34. 34.
    Rimando AM, Suh N (2008) Biological/chemopreventive activity of stilbenes and their effect on colon cancer. Planta Med 74:1635–1643PubMedCrossRefGoogle Scholar
  35. 35.
    Saiko P, Szakmary A, Jaeger W, Szekeres T (2008) Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res Rev Mutat Res 658:68–94Google Scholar
  36. 36.
    Schmidlin L, Poutaraud A, Claudel P, Mestre P, Prado E, Santos-Rosa M, Wiedemann-Merdinoglu S, Karst F, Merdinoglu D, Hugueney P (2008) A stress-inducible resveratrol O-methyltransferase involved in the biosynthesis of pterostilbene in grapevine. Plant Physiol 148:1630–1639PubMedCrossRefGoogle Scholar
  37. 37.
    Shankar S, Singh G, Srivastava RK (2007) Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci 12:4839–4854PubMedCrossRefGoogle Scholar
  38. 38.
    Suh N, Paul S, Hao X, Simi B, Xiao H, Rimando AM, Reddy BS (2007) Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats. Clin Cancer Res 13:350–355PubMedCrossRefGoogle Scholar
  39. 39.
    Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616PubMedCrossRefGoogle Scholar
  40. 40.
    van de Wetering K, Burkon A, Feddema W, Bot A, de Jonge H, Somoza V, Borst P (2009) Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol. Mol Pharmacol 75:876–885PubMedCrossRefGoogle Scholar
  41. 41.
    Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK (2004) High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32:1377–1382PubMedCrossRefGoogle Scholar
  42. 42.
    Wen X, Walle T (2006) Methylated flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab Dispos 34:1786–1792PubMedCrossRefGoogle Scholar
  43. 43.
    Wenzel E, Soldo T, Erbersdobler H, Somoza V (2005) Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res 49:482–494PubMedCrossRefGoogle Scholar
  44. 44.
    Wenzel E, Somoza V (2005) Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res 49:472–481PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Izet M. Kapetanovic
    • 1
  • Miguel Muzzio
    • 2
    Email author
  • Zhihua Huang
    • 2
  • Thomas N. Thompson
    • 3
  • David L. McCormick
    • 2
  1. 1.Division of Cancer PreventionNational Cancer InstituteBethesdaUSA
  2. 2.Life Sciences GroupIIT Research InstituteChicagoUSA
  3. 3.R&D Services Pharma ConsultingOmahaUSA

Personalised recommendations