Skip to main content
SpringerLink
Log in

Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

trans-4,4′-Dihydroxystilbene (DHS) is a naturally occurring resveratrol analog that displayed promising anti-cancer activities in pre-clinical studies. To further probe its therapeutic potential, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the measurement of DHS in rat plasma using electrospray ionization and multiple reaction monitoring in its negative ion mode. This analytical method demonstrated excellent linearity (R 2 > 0.99), selectivity, sensitivity (with a lower limit of quantification of 2.0 ng/mL), accuracy (both intra- and inter-day analytical recovery within 100 ± 15 %) and precision (both intra- and inter-day relative standard deviation within 10 %). The pharmacokinetic profiles of DHS were subsequently assessed in Sprague–Dawley rats. Following intravenous injection (4 mg/kg), DHS had a moderate apparent volume of distribution of the central compartment (V c  = 887 ± 297 mL/kg), clearance (Cl = 44.7 ± 5.1 mL/min/kg) and a relatively short mean transit time (MTT = 24.1 ± 8.8 min). When it was given as an oral suspension (10 mg/kg), DHS was absorbed slowly (t max 180 or 300 min) with very limited plasma exposure and absolute oral bioavailability (F = 2.22 ± 0.72 %). On the other hand, when DHS was fully solubilized by hydroxypropyl-β-cyclodextrin, it was absorbed rapidly (t max 30 or 45 min) with more than 15-fold increase in maximal plasma concentration (C max), plasma exposure (AUC 0→last) and bioavailability (F = 36.3 ± 4.8 %). Statistical comparison provided clear evidence that DHS was better than resveratrol from the perspective of pharmacokinetics. In conclusion, further explorations of DHS as an anti-cancer agent are warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5(6):493–506

    Article  CAS  Google Scholar 

  2. Smoliga JM, Baur JA, Hausenblas HA (2011) Resveratrol and health—a comprehensive review of human clinical trials. Mol Nutr Food Res 55(8):1129–1141

    Article  CAS  Google Scholar 

  3. Torres P, Avila JG, Romo de Vivar A, Garcia AM, Marin JC, Aranda E, Cespedes CL (2003) Antioxidant and insect growth regulatory activities of stilbenes and extracts from Yucca periculosa. Phytochemistry 64(2):463–473

    Article  CAS  Google Scholar 

  4. Zhao SK, Pu J, Chen YD, Li SX, Zhu YX, Li GP (2013) Chemical constituents of Swertia macrosperma. Zhong Cao Yao 44(18):2493–2497

    CAS  Google Scholar 

  5. Coppa T, Lazze MC, Cazzalini O, Perucca P, Pizzala R, Bianchi L, Stivala LA, Forti L, Maccario C, Vannini V, Savio M (2011) Structure-activity relationship of resveratrol and its analogue, 4,4′-dihydroxy-trans-stilbene, toward the endothelin axis in human endothelial cells. J Med Food 14(10):1173–1180

    Article  CAS  Google Scholar 

  6. Fan GJ, Liu XD, Qian YP, Shang YJ, Li XZ, Dai F, Fang JG, Jin XL, Zhou B (2009) 4,4′-Dihydroxy-trans-stilbene, a resveratrol analogue, exhibited enhanced antioxidant activity and cytotoxicity. Bioorg Med Chem 17(6):2360–2365

    Article  CAS  Google Scholar 

  7. Lappano R, Rosano C, Madeo A, Albanito L, Plastina P, Gabriele B, Forti L, Stivala LA, Iacopetta D, Dolce V, Ando S, Pezzi V, Maggiolini M (2009) Structure-activity relationships of resveratrol and derivatives in breast cancer cells. Mol Nutr Food Res 53(7):845–858

    Article  CAS  Google Scholar 

  8. Balan KV, Wang Y, Chen SW, Chen JC, Zheng LF, Yang L, Liu ZL, Pantazis P, Wyche JH, Han Z (2006) Proteasome-independent down-regulation of estrogen receptor-alpha (ERalpha) in breast cancer cells treated with 4,4′-dihydroxy-trans-stilbene. Biochem Pharmacol 72(5):573–581

    Article  CAS  Google Scholar 

  9. Cai YJ, Fang JG, Ma LP, Yang L, Liu ZL (2003) Inhibition of free radical-induced peroxidation of rat liver microsomes by resveratrol and its analogues. Biochim Biophys Acta 1637(1):31–38

    Article  CAS  Google Scholar 

  10. Maccario C, Savio M, Ferraro D, Bianchi L, Pizzala R, Pretali L, Forti L, Stivala LA (2012) The resveratrol analog 4,4′-dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells. Carcinogenesis 33(11):2172–2180

    Article  CAS  Google Scholar 

  11. Savio M, Coppa T, Bianchi L, Vannini V, Maga G, Forti L, Cazzalini O, Lazze MC, Perucca P, Prosperi E, Stivala LA (2009) The resveratrol analogue 4,4′-dihydroxy-trans-stilbene inhibits cell proliferation with higher efficiency but different mechanism from resveratrol. Int J Biochem Cell Biol 41(12):2493–2502

    Article  CAS  Google Scholar 

  12. Kimura Y, Sumiyoshi M, Baba K (2008) Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci 99(10):2083–2096

    CAS  Google Scholar 

  13. Lin JH, Lu AY (1997) Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 49(4):403–449

    CAS  Google Scholar 

  14. Yeo SC, Luo W, Wu J, Ho PC, Lin HS (2013) Quantification of pinosylvin in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pre-clinical pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 931:68–74

    Article  CAS  Google Scholar 

  15. NACLAR (2004) Guidelines on the Care and Use of Animals for Scientific Purposes. http://www.ava.gov.sg/NR/rdonlyres/C64255C0-3933-4EBC-B869-84621A9BF682/13557/Attach3_AnimalsforScientificPurposes.PDF.

  16. Lin HS, Ho PC (2011) Preclinical pharmacokinetic evaluation of resveratrol trimethyl ether in sprague-dawley rats: the impacts of aqueous solubility, dose escalation, food and repeated dosing on oral bioavailability. J Pharm Sci 100(10):4491–4500

    Article  CAS  Google Scholar 

  17. Lin HS, Spatafora C, Tringali C, Ho PC (2012) Determination of trans-2,4,3′,4′,5′-pentamethoxystilbene in rat plasma and its application to a pharmacokinetic study. J Pharm Biomed Anal 57:94–98

    Article  Google Scholar 

  18. Lin HS, Sviripa VM, Watt DS, Liu C, Xiang TX, Anderson BD, Ong PS, Ho PC (2013) Quantification of trans-2,6-difluoro-4′-N, N-dimethylaminostilbene in rat plasma: application to a pharmacokinetic study. J Pharm Biomed Anal 72:115–120

    Article  CAS  Google Scholar 

  19. Yeo SC, Ho PC, Lin HS (2013) Pharmacokinetics of pterostilbene in Sprague-Dawley rats: the impacts of aqueous solubility, fasting, dose escalation, and dosing route on bioavailability. Mol Nutr Food Res 57(6):1015–1025

    Article  CAS  Google Scholar 

  20. Choo QY, Yeo SC, Ho PC, Tanaka Y, Lin HS (2014) Pterostilbene surpassed resveratrol for anti-inflammatory application: potency consideration and pharmacokinetics perspective. J Funct Foods 11:352–362

    Article  CAS  Google Scholar 

  21. 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(11):2593–2600

    Article  CAS  Google Scholar 

  22. Muzzio M, Huang Z, Hu SC, Johnson WD, McCormick DL, Kapetanovic IM (2012) Determination of resveratrol and its sulfate and glucuronide metabolites in plasma by LC-MS/MS and their pharmacokinetics in dogs. J Pharm Biomed Anal 59:201–208

    Article  CAS  Google Scholar 

  23. Lou BS, Wu PS, Hou CW, Cheng FY, Chen JK (2014) Simultaneous quantification of trans-resveratrol and its sulfate and glucuronide metabolites in rat tissues by stable isotope-dilution UPLC-MS/MS analysis. J Pharm Biomed Anal 94:99–105

    Article  CAS  Google Scholar 

  24. Tian F, Wei H, Jia T, Tian H (2014) An improved highly sensitive method to determine low oxyresveratrol concentrations in rat plasma and its pharmacokinetic application. Biomed Chromatogr 28(5):667–672

    Article  CAS  Google Scholar 

  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(1):369–373

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research work was carried out under the financial support from a startup grant awarded from the National University of Singapore (R-148-000-174-133). SCMY is an awardee of the President’s Graduate Fellowship of the National University of Singapore. MGAAE is a recipient of the Singapore International Graduate Award.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore, 119260, Singapore

      Wan Chen, Samuel Chao Ming Yeo, Mai Gamal Ahmed Ahmed Elhennawy & Hai-Shu Lin

    2. Department of Clinical Pharmacy, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China

      Xiaoqiang Xiang

    Authors
    1. Wan Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Samuel Chao Ming Yeo
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Mai Gamal Ahmed Ahmed Elhennawy
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiaoqiang Xiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Hai-Shu Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hai-Shu Lin.

    Additional information

    Wan Chen and Samuel Chao Ming Yeo contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, W., Yeo, S.C.M., Elhennawy, M.G.A.A. et al. Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. Anal Bioanal Chem 407, 5793–5801 (2015). https://doi.org/10.1007/s00216-015-8762-7

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00216-015-8762-7

    Keywords

    Search

    Navigation