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Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 3, pp 679–689 | Cite as

Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice

  • Liu ZhongfaEmail author
  • Ming Chiu
  • Jiang Wang
  • Wei Chen
  • Winston Yen
  • Patty Fan-Havard
  • Lisa D. Yee
  • Kenneth K. Chan
Original Article

Abstract

Purpose

Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice.

Methods

This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC–MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software.

Results

A tenfold increase in the AUC 0→24h and more than 40-fold increase in the C max in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC.

Conclusion

This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo.

Keywords

Nano-emulsion curcumin (NEC) Pharmacokinetics Curcuminoids Curcumin metabolites LC–MS/MS 

Abbreviations

PEG

Polyethylene glycol

NEC

Nano-emulsion curcumin

SC

Suspension curcumin

PK

Pharmacokinetic

MP

Mobile phase

LC

Liquid chromatography

MS/MS

Tandem mass spectrometric detection

I.S.

Internal standard

CV

Coefficient of variation

ULAR

University laboratory animal resources

XIC

Extract ion mass chromatograms

SD

Solid disperse

Notes

Acknowledgments

This work was supported by National Institute of Health (NIH) grants [R21 CA135478] (Zhongfa Liu) and Biomedical Mass Spectrometric Laboratory (Kenneth K. Chan and Zhongfa Liu) at The Ohio State University.

Conflict of interest

The contents of this manuscript have been submitted for a patent application.

References

  1. 1.
    Lopez-Lazaro M (2008) Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol Nutr Food Res 52(Suppl 1):S103–S127PubMedGoogle Scholar
  2. 2.
    Hsu CH, Cheng AL (2007) Clinical studies with curcumin. Adv Exp Med Biol 595:471–480PubMedCrossRefGoogle Scholar
  3. 3.
    Pan MH, Huang TM, Lin JK (1999) Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos Biol Fate Chem 27:486–494PubMedGoogle Scholar
  4. 4.
    Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric Z, Brenner DE (2008) Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev 17:1411–1417PubMedCrossRefGoogle Scholar
  5. 5.
    Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, Williams ML, Steward WP, Gescher AJ (2002) Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse: a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev 11:535–540PubMedGoogle Scholar
  6. 6.
    Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W et al (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900PubMedGoogle Scholar
  7. 7.
    Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64:353–356PubMedCrossRefGoogle Scholar
  8. 8.
    Thangapazham RL, Puri A, Tele S, Blumenthal R, Maheshwari RK (2008) Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells. Int J Oncol 32:1119–1123PubMedGoogle Scholar
  9. 9.
    Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, Zhai G (2009) Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm 371:148–155PubMedCrossRefGoogle Scholar
  10. 10.
    Gao Y, Li Z, Sun M, Li H, Guo C, Cui J, Li A, Cao F, Xi Y, Lou H et al (2010) Preparation, characterization, pharmacokinetics, and tissue distribution of curcumin nanosuspension with TPGS as stabilizer. Drug Dev Ind Pharm 36:1225–1234PubMedCrossRefGoogle Scholar
  11. 11.
    Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG (2010) Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem 58:2095–2099PubMedCrossRefGoogle Scholar
  12. 12.
    Ma Z, Shayeganpour A, Brocks DR, Lavasanifar A, Samuel J (2007) High-performance liquid chromatography analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar formulation of curcumin. Biomed Chromatogr 21:546–552PubMedCrossRefGoogle Scholar
  13. 13.
    Mach CM, Chen JH, Mosley SA, Kurzrock R, Smith JA (2010) Evaluation of liposomal curcumin cytochrome p450 metabolism. Anticancer Res 30:811–814PubMedGoogle Scholar
  14. 14.
    Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK (2007) Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm 330:155–163PubMedCrossRefGoogle Scholar
  15. 15.
    Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ (2007) Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol 60:171–177PubMedCrossRefGoogle Scholar
  16. 16.
    Mohanty C, Acharya S, Mohanty AK, Dilnawaz F, Sahoo SK (2010) Curcumin-encapsulated MePEG/PCL diblock copolymeric micelles: a novel controlled delivery vehicle for cancer therapy. Nanomed (Lond, Engl) 5:433–449CrossRefGoogle Scholar
  17. 17.
    Mohanty C, Sahoo SK (2010) The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials 31:6597–6611PubMedCrossRefGoogle Scholar
  18. 18.
    Mukerjee A, Vishwanatha JK (2009) Formulation, characterization and evaluation of curcumin-loaded PLGA nanospheres for cancer therapy. Anticancer Res 29:3867–3875PubMedGoogle Scholar
  19. 19.
    Onoue S, Takahashi H, Kawabata Y, Seto Y, Hatanaka J, Timmermann B, Yamada S (2010) Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. J Pharm Sci 99:1871–1881PubMedGoogle Scholar
  20. 20.
    Shahani K, Swaminathan SK, Freeman D, Blum A, Ma L, Panyam J (2010) Injectable sustained release micro particles of curcumin: a new concept for cancer chemoprevention. Cancer Res 70:4443–4452PubMedCrossRefGoogle Scholar
  21. 21.
    Yallapu MM, Gupta BK, Jaggi M, Chauhan SC (2009) Fabrication of curcumin encapsulated PLGA nanoparticles for improved therapeutic effects in metastatic cancer cells. J Colloid Interface Sci 351:19–29CrossRefGoogle Scholar
  22. 22.
    Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, Zhai G (2009) Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm 371(1–2):148–155PubMedCrossRefGoogle Scholar
  23. 23.
    Mosley CA, Liotta DC, Snyder JP (2007) Highly active anticancer curcumin analogues. Adv Exp Med Biol 595:77–103PubMedCrossRefGoogle Scholar
  24. 24.
    Ohtsu H, Xiao Z, Ishida J, Nagai M, Wang HK, Itokawa H, Su CY, Shih C, Chiang T, Chang E et al (2002) Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents. J Med Chem 45:5037–5042PubMedCrossRefGoogle Scholar
  25. 25.
    Kurien BT, Singh A, Matsumoto H, Scofield RH (2007) Improving the solubility and pharmacological efficacy of curcumin by heat treatment. Assay Drug Dev Technol 5:567–576PubMedCrossRefGoogle Scholar
  26. 26.
    Tomren MA, Masson M, Loftsson T, Tonnesen HH (2007) Studies on curcumin and curcuminoids XXXI. Symmetric and asymmetric curcuminoids: stability, activity and complexation with cyclodextrin. Int J Pharm 338:27–34PubMedCrossRefGoogle Scholar
  27. 27.
    Barik A, Priyadarsini KI, Mohan H (2003) Photophysical studies on binding of curcumin to bovine serum albumins. Photochem Photobiol 77:597–603PubMedCrossRefGoogle Scholar
  28. 28.
    Vijaya Saradhi UV, Ling Y, Wang J, Chiu M, Schwartz EB, Fuchs JR, Chan KK, Liu Z (2010) A liquid chromatography-tandem mass spectrometric method for quantification of curcuminoids in cell medium and mouse plasma. J Chromatogr 878:3045–3051CrossRefGoogle Scholar
  29. 29.
    Lin JK, Pan MH, Lin-Shiau SY (2000) Recent studies on the biofunctions and biotransformations of curcumin. Biofactors (Oxf, Engl) 13:153–158CrossRefGoogle Scholar
  30. 30.
    Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S, Yu J, Li PK, Lin J, Fuchs JR, Marcucci G et al (2009) Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett 19:706–709PubMedCrossRefGoogle Scholar
  31. 31.
    Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A, Maitra A (2007) Polymeric nanoparticles-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnol 5:3CrossRefGoogle Scholar
  32. 32.
    Xu DH, Wang S, Mei XT, Luo XJ, Xu SB (2008) Studies on solubility enhancement of curcumin by polyvinylpyrrolidione K30. Zhong Yao Cai = Zhong Yao Cai = J Chin Med Mater 31:438–442Google Scholar
  33. 33.
    Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B et al (2008) Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther 326:196–208PubMedCrossRefGoogle Scholar
  34. 34.
    Woo JS, Song YK, Hong JY, Lim SJ, Kim CK (2008) Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers. Eur J Pharm Sci 33:159–165PubMedCrossRefGoogle Scholar
  35. 35.
    Patel D, Sawant KK (2007) Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS). Drug Dev Ind Pharm 33:1318–1326PubMedCrossRefGoogle Scholar
  36. 36.
    Wang DK, Shi ZH, Liu L, Wang XY, Zhang CX, Zhao P (2006) Development of self-microemulsifying drug delivery systems for oral bioavailability enhancement of alpha-asarone in beagle dogs. PDA J Pharm Sci Technol/PDA 60:343–349Google Scholar
  37. 37.
    Dempe JS, Pfeiffer E, Grimm AS, Metzler M (2008) Metabolism of curcumin and induction of mitotic catastrophe in human cancer cells. Mol Nutr Food Res 52:1074–1081PubMedCrossRefGoogle Scholar
  38. 38.
    Hoehle SI, Pfeiffer E, Metzler M (2007) Glucuronidation of curcuminoids by human microsomal and recombinant UDP-glucuronosyltransferases. Mol Nutr Food Res 51:932–938PubMedCrossRefGoogle Scholar
  39. 39.
    Pfeiffer E, Hoehle SI, Walch SG, Riess A, Solyom AM, Metzler M (2007) Curcuminoids form reactive glucuronides in vitro. J Agric Food Chem 55:538–544PubMedCrossRefGoogle Scholar
  40. 40.
    Matsunaga T, Endo S, Soda M, Zhao HT, El-Kabbani O, Tajima K, Hara A (2009) Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: probing the active site of the enzyme with molecular modeling and site-directed mutagenesis. Biochem Biophys Research Commun 389:128–132CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Liu Zhongfa
    • 1
    • 2
    Email author
  • Ming Chiu
    • 1
  • Jiang Wang
    • 1
  • Wei Chen
    • 1
  • Winston Yen
    • 1
  • Patty Fan-Havard
    • 4
  • Lisa D. Yee
    • 5
  • Kenneth K. Chan
    • 1
    • 2
    • 3
  1. 1.College of PharmacyThe Ohio State UniversityColumbusUSA
  2. 2.Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  3. 3.College of Medicine and Public HealthThe Ohio State UniversityColumbusUSA
  4. 4.School of Pharmacy and Pharmaceutical SciencesThe State University of New YorkAmherstUSA
  5. 5.The Department of SurgeryThe Ohio State UniversityColumbusUSA

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