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Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats

European Journal of Drug Metabolism and Pharmacokinetics volume 41, pages 777–785 (2016)Cite this article

Abstract

Background and Objectives

Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin.

Methods

The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry.

Results

The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation.

Conclusion

Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

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References

  1. Howe E, Keiwkarnka B, Khan MI. Traditional medicine and medicinal plants: utilization, policy and research in Thailand. J Public Health. 2004;2:102.

    Google Scholar 

  2. Satyapan N, Patarakitvanit S, Temboonkiet S, Vudhironarit T, Tankanitlert J. Herbal medicine: affecting factors and prevalence of use among Thai population in Bangkok. J Med Assoc Thai. 2010;93:S139–44.

    PubMed  Google Scholar 

  3. Prasad S, Aggarwal BB. Turmeric, the golden spice: from traditional medicine to modern medicine. In: Benzie IFF, Wachtel-Galor S, editors. Herbal medicine: biomolecular and clinical aspects. 2nd ed. Boca Raton:CRC Press;2011.

  4. Ammon HP, Wahl MA. Pharmacology of Curcuma longa. Planta Med. 1991;57:1–7.

    CAS  Article  PubMed  Google Scholar 

  5. Department of Medical Sciences. Thai herbal pharmacopoeia, vol. I. Bangkok: Prachachon; 2009.

    Google Scholar 

  6. Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B, et al. Biological activities of curcumin and its analogues (congeners) made by man and mother nature. Biochem Pharmacol. 2008;76:1590–611.

    CAS  Article  PubMed  Google Scholar 

  7. Huang MT, Newmark HL, Frenkel K. Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem. 1997;27:S26–34.

    Article  Google Scholar 

  8. Pubchem Compound. Cited on 8 August 2014 by using search term “Curcumin” https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=969516&loc=ec_rcs.

  9. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology. 1980;16:259–65.

    CAS  Article  PubMed  Google Scholar 

  10. Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos. 1999;27:486–94.

    CAS  PubMed  Google Scholar 

  11. Zhongfa L, Chiu M, Wang J, Chen W, Yen W, Fan-Havard P, et al. Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice. Cancer Chemother Pharmacol. 2012;69:679–89.

    Article  PubMed  Google Scholar 

  12. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4:807–18.

    CAS  Article  PubMed  Google Scholar 

  13. Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC/MS/MS. J Chromatogr B. 2007;853:183–9.

    CAS  Article  Google Scholar 

  14. Heger M, van Golen RF, Broekgaarden M, Michel MC. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer. Pharmacol Rev. 2014;66:222–307.

    Article  PubMed  Google Scholar 

  15. Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005;7:E118–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Ni Z, Bikadi Z, Rosenberg MF, Mao Q. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab. 2010;11:603–17.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Gupta NK, Dixit VK. Bioavailability enhancement of curcumin by complexation with phosphatidyl choline. J Pharm Sci. 2011;100:1987–95.

    CAS  Article  PubMed  Google Scholar 

  18. Liu A, Lou H, Zhao L, Fan P. Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. J Pharm Biomed Anal. 2006;40:720–7.

    CAS  Article  PubMed  Google Scholar 

  19. Zhang W, Tan TM, Lim LY. Impact of curcumin-induced changes in p-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos. 2007;35:110–5.

    Article  PubMed  Google Scholar 

  20. Liang G, Yang S, Zhou H, Shao L, Huang K, Xiao J, et al. Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues. Eur J Med Chem. 2009;44:915–9.

    CAS  Article  PubMed  Google Scholar 

  21. Rinwa P, Kumar A. Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice. Brain Res. 2012;1488:38–50.

    CAS  Article  PubMed  Google Scholar 

  22. Steward WP, Gescher AJ. Curcumin in cancer management: recent results of analogue design and clinical studies and desirable future research. Mol Nutr Food Res. 2008;52:1005–9.

    CAS  Article  PubMed  Google Scholar 

  23. Wichitnithad W, Nimmannit U, Wacharasindhu S, Rojsitthisak P. Synthesis, characterization and biological evaluation of succinate prodrugs of curcuminoids for colon cancer treatment. Molecules. 2011;16:1888–900.

    CAS  Article  PubMed  Google Scholar 

  24. Wongsrisakul J, Wichitnithad W, Rojsitthisak P, Towiwat P. Antinociceptive effects of CDD in animals models. J Health Res. 2010;24:175–80.

    CAS  Google Scholar 

  25. Fan J, Lannoy IAM. Pharmacokinetics. Biochem Pharmacol. 2014;87:93–120.

    CAS  Article  PubMed  Google Scholar 

  26. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure–function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther. 2008;326:196–208.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacologica et Toxicologica. 1978;43:86–92.

    CAS  Article  PubMed  Google Scholar 

  28. Balant LP, Doelker E, Buri P. Prodrugs for the improvement of drug absorption via different routes of administration. Eur J Drug Metab Pharmacokinet. 1990;15:143–53.

    CAS  Article  PubMed  Google Scholar 

  29. 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;64:353–6.

    CAS  Article  PubMed  Google Scholar 

  30. Ajazuddin, Alexander A, Qureshi A, Kumari L, Vaishnav P, Sharma M, et al. Role of herbal bioactives as a potential bioavailability enhancer for active pharmaceutical ingredients. Fitoterapia. 2014;97C:1–14.

  31. Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci. 2000;67:2785–93.

    CAS  Article  PubMed  Google Scholar 

  32. Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, et al. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomark Prev. 2002;11:105–11.

    CAS  Google Scholar 

  33. Limtrakul P. Curcumin as chemosensitizer. Adv Exp Med Biol. 2007;595:269–300.

    Article  PubMed  Google Scholar 

  34. Parkinson A, Ogilvie BW. Biotransformation of xenobiotics. In: Klaassen CD, editor. Casarette and Doull’s toxicology; the basic sciences of poisons. 7th ed. New York: McGraw-Hill; 2007. p. 161–304.

    Google Scholar 

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Acknowledgments

The technical language amendment was supervised by Dr. Ian S. Haworth, Dr. Jessica T. Lin and Dr. Delia Bethell.

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Affiliations

  1. Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

    Kunan Bangphumi, Chuleeporn Kittiviriyakul, Pasarapa Towiwat & Phisit Khemawoot

  2. Graduate School of Chulalongkorn University, Chulalongkorn University, Bangkok, Thailand

    Kunan Bangphumi & Chuleeporn Kittiviriyakul

  3. Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

    Pornchai Rojsitthisak

  4. Chulalongkorn University Drugs and Health Product Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

    Pasarapa Towiwat, Pornchai Rojsitthisak & Phisit Khemawoot

Authors
  1. Kunan Bangphumi
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  2. Chuleeporn Kittiviriyakul
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  3. Pasarapa Towiwat
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  4. Pornchai Rojsitthisak
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  5. Phisit Khemawoot
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Corresponding author

Correspondence to Phisit Khemawoot.

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Funding

This research was supported by the Ratchadaphiseksomphot Endowment Fund 2013 of Chulalongkorn University, CU-56-329-HR. Dr. Kunan Bangphumi was working under the Postdoctoral Scholarship of Ratchadaphiseksomphot Endowment Fund of Chulalongkorn University.

Conflicts of interest

All authors declare no conflict of interest.

Ethical approval

Animal procedures complied with the guidelines of the Institutional Animal Care and Use Committee of Chulalongkorn University, approval number 13-33-008.

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Bangphumi, K., Kittiviriyakul, C., Towiwat, P. et al. Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats. Eur J Drug Metab Pharmacokinet 41, 777–785 (2016). https://doi.org/10.1007/s13318-015-0308-z

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  • DOI: https://doi.org/10.1007/s13318-015-0308-z

Keywords

  • Curcumin
  • Oral Bioavailability
  • Glucuronide Conjugate
  • Plasma Ratio
  • Pass Metabolism