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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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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Acknowledgments

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

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Authors and 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

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