Advertisement

Pharmaceutical Research

, 28:1606 | Cite as

Population Pharmacokinetic Modeling of trans-Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats

  • Helena Colom
  • Irene Alfaras
  • Mònica Maijó
  • M. Emília Juan
  • Joana M. Planas
Research Paper

ABSTRACT

Purpose

To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates.

Methods

Male Sprague–Dawley rats were administered i.v. and p.o. with 2, 10 and 20 mg·kg−1 of trans-resveratrol. Blood was collected at different times during 24 h. An integrated PK model was developed using a sequential analysis, with non-linear mixed effect modeling (NONMEM). A prediction-corrected visual predictive check (pcVPC) was used to assess model performance. The model predictive capability was also evaluated with simulations after the i.v. administration of 15 mg·kg−1 that were compared with an external data set.

Results

Disposition PK of trans-resveratrol and its metabolites was best described by a three-linked two-compartment model. Clearance of trans-resveratrol by conversion to its conjugates occurred by a first-order process, whereas both metabolites were eliminated by parallel first-order and Michaelis-Menten kinetics. The pcVPC confirmed the model stability and precision. The final model was successfully applied to the external data set showing its robustness.

Conclusions

A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.

KEY WORDS

glucuronide and sulfate conjugates NONMEM polyphenols population pharmacokinetics trans-resveratrol 

ABBREVIATIONS

ABC

ATP-binding cassette

AIC

Akaike information criterion

AUC

area under the curve

BCRP

breast cancer resistance protein

DV

observed concentrations

IAV

inter-animal variability

IPRED

individual model predicted concentrations

MRP

multidrug resistance protein

OFV

objective function value

pcVPC

prediction corrected visual predictive check

PD

pharmacodynamic

PK

pharmacokinetic

PRED

population model predicted concentrations

RSE

relative standard error

UGT

UDP-glucuronosyltransferase

Notes

ACKNOWLEDGMENTS

This study was supported by the Ministerio de Ciencia y Tecnología grants AGL2005-05728 and AGL2009-12866 and the Generalitat de Catalunya grants 2005-SGR-00632 and 2009-SGR-00471.

REFERENCES

  1. 1.
    Pervaiz S, Holme AL. Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal. 2009;11(11):2851–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Brisdelli F, D’Andrea G, Bozzi A. Resveratrol: a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab. 2009;10(6):530–46.PubMedGoogle Scholar
  3. 3.
    Juan ME, Vinardell MP, Planas JM. The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J Nutr. 2002;132(2):257–60.PubMedGoogle Scholar
  4. 4.
    Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res. 2010;54(1):7–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Juan ME, Buenafuente J, Casals I, Planas JM. Plasmatic levels of trans-resveratrol in rats. Food Res Int. 2002;35(2–3):195–9.CrossRefGoogle Scholar
  6. 6.
    Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302(1):369–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Sale S, Verschoyle RD, Boocock D, Jones DJ, Wilsher N, Ruparelia KC, et al. Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3, 4, 5, 4′-tetramethoxystilbene. Br J Cancer. 2004;90(3):736–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, et al. Phase I dose escalation PK study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomark Prev. 2007;16(6):1246–52.CrossRefGoogle Scholar
  9. 9.
    Almeida L, Vaz-da-Silva M, Falcão A, Soares E, Costa R, Loureiro AI, et al. PK and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res. 2009;53 Suppl 1:S7–15.PubMedCrossRefGoogle Scholar
  10. 10.
    Nunes T, Almeida L, Rocha JF, Falcão A, Fernandes-Lopes C, Loureiro AI, et al. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol. 2009;49(12):1477–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Juan ME, González-Pons E, Planas JM. Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. J Nutr. 2010;140(3):489–95.PubMedCrossRefGoogle Scholar
  12. 12.
    Hebbar V, Shen G, Hu R, Kim BR, Chen C, Korytko PJ, et al. Toxicogenomics of resveratrol in rat liver. Life Sci. 2005;76(20):2299–314.PubMedCrossRefGoogle Scholar
  13. 13.
    Lançon A, Hanet N, Jannin B, Delmas D, Heydel JM, Lizard G, et al. Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes. Drug Metab Dispos. 2007;35(5):699–703.PubMedCrossRefGoogle Scholar
  14. 14.
    Alfaras I, Pérez M, Juan ME, Merino G, Prieto JG, Planas JM, et al. Involvement of breast cancer resistance protein (BCRP1/ABCG2) in the bioavailability and tissue distribution of trans-resveratrol in knockout mice. J Agric Food Chem. 2010;58(7):4523–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Juan ME, Maijó M, Planas JM. Quantification of trans-resveratrol and its metabolites in rat plasma and tissues by HPLC. J Pharm Biomed Anal. 2010;51(2):391–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Hem A, Smith AJ, Solberg P. Saphenous vein puncture for blood sampling of the mouse, rat, hamster, gerbil, guinea pig, ferret and mink. Lab Anim. 1998;32(4):364–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Beal SL, Sheiner LB. NONMEM User’s guide. Icon Development Solutions: Ellicot City, MD 1989–2006.Google Scholar
  18. 18.
    Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Meth Programs Biomed. 1999;58(1):51–64.CrossRefGoogle Scholar
  19. 19.
    Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit: a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Meth Programs Biomed. 2005;79(3):241–57.CrossRefGoogle Scholar
  20. 20.
    Yamaoka T, Nakagawa T. Uno, Application of Akaike’s Information Criterion (AIC) in the evaluation of linear pharmacokinetics equations. J Pharmacokinet Biopharm. 1978;6(2):165–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Karlsson MO, Holford NH. A Tutorial on Visual Predictive Checks. 2008, pp 17 (Abstract 1434). Available at: http://www.page-meeting.org/?abstract=1434.
  22. 22.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-Corrected Visual Predictive Checks for Diagnosing Nonlinear Mixed-Effects Models. AAPS J. 2011. doi: 10.1208/s12248-011-9255-z.
  23. 23.
    Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11(3):558–69.PubMedCrossRefGoogle Scholar
  24. 24.
    van de Wetering K, Burkon A, Feddema W, Bot A, de Jonge H, Somoza V, et al. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    de Santi C, Pietrabissa A, Mosca F, Pacifici GM. Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica. 2000;30(11):1047–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Sabolovic N, Humbert AC, Radominska-Pandya A, Magdalou J. Resveratrol is efficiently glucuronidated by UDP-glucuronosyltransferases in the human gastrointestinal tract and in Caco-2 cells. Biopharm Drug Dispos. 2006;27(4):181–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Maier-Salamon A, Hagenauer B, Reznicek G, Szekeres T, Thalhammer T, Jäger W. Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides. J Pharm Sci. 2008;97(4):1615–28.PubMedCrossRefGoogle Scholar
  28. 28.
    Andlauer W, Kolb J, Siebert K, Fürst P. Assessment of resveratrol bioavailability in the perfused small intestine of the rat. Drugs Exp Clin Res. 2000;26(2):47–55.PubMedGoogle Scholar
  29. 29.
    Kuhnle G, Spencer JP, Chowrimootoo G, Schroeter H, Debnam ES, Srai SK, et al. Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Biochem Biophys Res Commun. 2000;272(1):212–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Helena Colom
    • 1
  • Irene Alfaras
    • 2
  • Mònica Maijó
    • 2
  • M. Emília Juan
    • 2
  • Joana M. Planas
    • 2
  1. 1.Departament de Farmàcia i Tecnologia Farmacèutica Facultat de FarmàciaUniversitat de BarcelonaBarcelonaSpain
  2. 2.Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB)Universitat de BarcelonaBarcelonaSpain

Personalised recommendations