Curcumin, a golden spice with a low bioavailability

Abstract In recent years several drugs have been developed deriving from traditional products and current drug research is actively investigating the possible therapeutic roles of many Ayurvedic and Traditional Chinese Medicinal remedies. Prominent among those being examined is turmeric. Its main active ingredient is curcumin (C). Curcumin acts as an antioxidant, anti-inflammatory, anticarcinoma, antimicrobial, antiviral, hypoglycemic and wound healer. It has shown therapeutic efficacy in numerous chronic diseases and in some kinds of cancer in vitro and in vivo . Despite much evidence of its efficacy and safety, curcumin has not yet been approved as a therapeutic agent due to its low bioavailability, instability at physiological pH, insolubility in water, slow uptake by cells and rapid metabolism inside cells. The aim of this review is to summarize the pharmacodynamic and pharmacokinetic characteristics of curcumin and to compare the different pharmaceutical strategies employed to increase its bioavailability.

[1]  M. Krishna,et al.  Curcumin mediates time and concentration dependent regulation of redox homeostasis leading to cytotoxicity in macrophage cells. , 2009, European journal of pharmacology.

[2]  D. G. Walters,et al.  Effect of butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole on cytochrome P450 forms in cultured human hepatocytes , 2008 .

[3]  K. Abel,et al.  Evaluation in vitro of synthetic curcumins as agents promoting monocytic gene expression related to β-amyloid clearance. , 2012, Chemical research in toxicology.

[4]  H. Inoue,et al.  Compounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymes , 2011, Journal of Natural Medicines.

[5]  S. Jee,et al.  Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. , 2001, Anticancer research.

[6]  M. Fujita,et al.  Innovative preparation of curcumin for improved oral bioavailability. , 2011, Biological & pharmaceutical bulletin.

[7]  T. Chiba,et al.  Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers , 2011, Cancer Chemotherapy and Pharmacology.

[8]  K. S. Kumar,et al.  Turmeric: a herbal and traditional medicine. , 2009 .

[9]  U. Zutshi,et al.  Permeability characteristics of piperine on oral absorption--an active alkaloid from peppers and a bioavailability enhancer. , 1998, Indian journal of experimental biology.

[10]  S. Vareed,et al.  Pharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human Subjects , 2008, Cancer Epidemiology Biomarkers & Prevention.

[11]  G. Zhai,et al.  Preparation and in vivo pharmacokinetics of curcumin-loaded PCL-PEG-PCL triblock copolymeric nanoparticles , 2012, International journal of nanomedicine.

[12]  Ying-zheng Zhao,et al.  Physical characterization and cellular uptake of propylene glycol liposomes in vitro , 2012, Drug development and industrial pharmacy.

[13]  D. Knopman,et al.  Alternative Medicine and Alzheimer Disease , 2008, The neurologist.

[14]  Catherine A. Sugar,et al.  Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study , 2012, Alzheimer's Research & Therapy.

[15]  L. Lim,et al.  In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. , 2008, Toxicology and applied pharmacology.

[16]  L. Yee,et al.  Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice , 2012, Cancer Chemotherapy and Pharmacology.

[17]  M. Amiri,et al.  Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: results of a randomised, double-blind, placebo-controlled trial , 2011, British Journal of Nutrition.

[18]  Kristin N. Baglole,et al.  Fluorescence enhancement of curcumin upon inclusion into parent and modified cyclodextrins , 2005 .

[19]  W. Hsu,et al.  Inhibition of Enveloped Viruses Infectivity by Curcumin , 2013, PloS one.

[20]  Fazli Wahid,et al.  Curcumin in Cancer Chemoprevention: Molecular Targets, Pharmacokinetics, Bioavailability, and Clinical Trials , 2010, Archiv der Pharmazie.

[21]  B. Aggarwal,et al.  Targeting TNF for Treatment of Cancer and Autoimmunity. , 2009, Advances in experimental medicine and biology.

[22]  H. Ahsan,et al.  Strand scission in DNA induced by curcumin in the presence of Cu(II). , 1998, Cancer letters.

[23]  Jen-kun Lin,et al.  Curcumin: a Potential Cancer Chemopreventive Agent through Suppressing NF-κB Signaling , 2008 .

[24]  P. Kidd.  Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts. , 2009, Alternative medicine review : a journal of clinical therapeutic.

[25]  A. Holmgren,et al.  Thioredoxin Reductase Is Irreversibly Modified by Curcumin , 2005, Journal of Biological Chemistry.

[26]  H. Ahsan,et al.  Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. , 1999, Chemico-biological interactions.

[27]  A. Dinda,et al.  Polycaprolactone diacrylate crosslinked biodegradable semi-interpenetrating networks of polyacrylamide and gelatin for controlled drug delivery , 2010, Biomedical materials.

[28]  Sanjeev Banerjee,et al.  Curcumin Synergizes With Resveratrol to Inhibit Colon Cancer , 2009, Nutrition and cancer.

[29]  G. Appendino,et al.  Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. , 2011, Journal of natural products.

[30]  Hong Wang,et al.  Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation. , 2014, Molecular medicine reports.

[31]  S. Marathe,et al.  Multifaceted roles of curcumin: two sides of a coin! , 2011, Expert opinion on biological therapy.

[32]  Bharat B. Aggarwal,et al.  Epigenetic changes induced by curcumin and other natural compounds , 2011, Genes & Nutrition.

[33]  Jen-kun Lin,et al.  Stability of curcumin in buffer solutions and characterization of its degradation products. , 1997, Journal of pharmaceutical and biomedical analysis.

[34]  M. R. Kumar,et al.  Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[35]  S. Khopde,et al.  Inhibition of Radiation-Induced Lipid Peroxidation by Tetrahydrocurcumin: Possible Mechanisms by Pulse Radiolysis , 2000, Bioscience, biotechnology, and biochemistry.

[36]  Jhi-Joung Wang,et al.  Efficacy and irritancy of enhancers on the in‐vitro and in‐vivo percutaneous absorption of curcumin , 2003, The Journal of pharmacy and pharmacology.

[37]  R. Benya,et al.  Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia , 2011, Cancer Prevention Research.

[38]  Dean P. Jones,et al.  EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism , 2005, Anti-cancer drugs.

[39]  D. Greenblatt,et al.  Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers , 2013, British journal of clinical pharmacology.

[40]  I. Kaur,et al.  Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. , 2011, Molecular nutrition & food research.

[41]  Ricky A. Sharma,et al.  Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[42]  A. Gescher,et al.  Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine , 2007, Cancer Chemotherapy and Pharmacology.

[43]  B. Aggarwal,et al.  Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. , 2010, Biochemical pharmacology.

[44]  Citra Ariani Edityaningrum,et al.  Molecular Inclusion Complex of Curcumin–β-Cyclodextrin Nanoparticle to Enhance Curcumin Skin Permeability from Hydrophilic Matrix Gel , 2013, AAPS PharmSciTech.

[45]  M. Bharath,et al.  Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: therapeutic implications for Parkinson's disease explained via in silico studies. , 2008, Free radical biology & medicine.

[46]  M. Kanai.  Therapeutic applications of curcumin for patients with pancreatic cancer. , 2014, World journal of gastroenterology.

[47]  Luciana Facco Dalmolin,et al.  Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG blend nanoparticles after oral administration in rats. , 2013, Colloids and surfaces. B, Biointerfaces.

[48]  R. Eckert,et al.  Green Tea Polyphenol and Curcumin Inversely Regulate Human Involucrin Promoter Activity via Opposing Effects on CCAAT/Enhancer-binding Protein Function* , 2004, Journal of Biological Chemistry.

[49]  B. Aggarwal,et al.  Curcumin: Getting Back to the Roots , 2005, Annals of the New York Academy of Sciences.

[50]  G. Blennow,et al.  A study on the fate of curcumin in the rat. , 2009, Acta pharmacologica et toxicologica.

[51]  I. Otsuka,et al.  Elaboration of chitosan-coated nanoparticles loaded with curcumin for mucoadhesive applications. , 2012, Journal of colloid and interface science.

[52]  D. Kitamoto,et al.  Characterization and Bioavailability of Liposomes Containing a Ukon Extract , 2008, Bioscience, biotechnology, and biochemistry.

[53]  H. Kishida,et al.  Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. , 2005, Journal of agricultural and food chemistry.

[54]  G. Feldmann,et al.  Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"): a novel strategy for human cancer therapy , 2007, Journal of nanobiotechnology.

[55]  Fengyi Zhang,et al.  PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms. , 2011, Journal of agricultural and food chemistry.

[56]  V. Ravindranath,et al.  Absorption and tissue distribution of curcumin in rats. , 1980, Toxicology.

[57]  A. Conney,et al.  Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. , 1991, Cancer research.

[58]  B. Goldin,et al.  Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. , 1997, Biochemical and biophysical research communications.

[59]  H. Tønnesen.  Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX. , 2006, Die Pharmazie.

[60]  Aiguo Li,et al.  Preparation, characterization, pharmacokinetics, and tissue distribution of curcumin nanosuspension with TPGS as stabilizer , 2010, Drug development and industrial pharmacy.

[61]  B. Aggarwal,et al.  Multitargeting by curcumin as revealed by molecular interaction studies. , 2011, Natural product reports.

[62]  Razelle Kurzrock,et al.  Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer , 2008, Clinical Cancer Research.

[63]  T. Kálai,et al.  Cellular uptake, retention and bioabsorption of HO-3867, a fluorinated curcumin analog with potential antitumor properties , 2010, Cancer biology & therapy.

[64]  G. Zhai,et al.  N-trimethyl chitosan chloride-coated liposomes for the oral delivery of curcumin , 2012, Journal of liposome research.

[65]  Jen-kun Lin,et al.  Biotransformation of curcumin through reduction and glucuronidation in mice. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[66]  Ashutosh Kumar Singh,et al.  Enhancement of wound healing by curcumin in animals , 1998, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[67]  S. Wexner,et al.  Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[68]  Xuemei Zhang,et al.  Effects of curcumin on ion channels and transporters , 2014, Front. Physiol..

[69]  T. Tsai,et al.  Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[70]  K. Chopra,et al.  CURCUMIN, THE ACTIVE PRINCIPLE OF TURMERIC (CURCUMA LONGA), AMELIORATES DIABETIC NEPHROPATHY IN RATS , 2006, Clinical and experimental pharmacology & physiology.

[71]  B. Aggarwal,et al.  Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals , 2010, Cancer and Metastasis Reviews.

[72]  S. Shishodia,et al.  Modulation of transcription factors by curcumin. , 2007, Advances in experimental medicine and biology.

[73]  Murali M. Yallapu,et al.  Fabrication of curcumin encapsulated PLGA nanoparticles for improved therapeutic effects in metastatic cancer cells. , 2010, Journal of colloid and interface science.

[74]  M. John,et al.  Development and pharmacokinetic evaluation of a curcumin co-solvent formulation. , 2013, Anticancer research.

[75]  J. Plummer,et al.  The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. , 1978, Xenobiotica; the fate of foreign compounds in biological systems.

[76]  M. Majeed,et al.  Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. , 1998, Planta medica.

[77]  A. Troxel,et al.  Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective clinical trial. , 2008, Journal of the American Academy of Dermatology.

[78]  Lie-Chwen Lin,et al.  Effects of polymer molecular weight on relative oral bioavailability of curcumin , 2012, International journal of nanomedicine.

[79]  Zhiwei Wang,et al.  NF-κB Signaling Pathway and Its Therapeutic Implications in Human Diseases , 2008, International reviews of immunology.

[80]  O. Sabzevari,et al.  Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. , 2002, Toxicology.

[81]  S. Yamada,et al.  Effects of dietary ingredients on function and expression of P-glycoprotein in human intestinal epithelial cells. , 2010, Biological & pharmaceutical bulletin.

[82]  M. Metzler,et al.  Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. , 2006, Journal of agricultural and food chemistry.

[83]  B. Aggarwal,et al.  Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). , 2007, Free radical biology & medicine.

[84]  S. Joyal,et al.  A Pilot Cross-Over Study to Evaluate Human Oral Bioavailability of BCM-95®CG (Biocurcumax™), A Novel Bioenhanced Preparation of Curcumin , 2008, Indian journal of pharmaceutical sciences.

[85]  J. Cashman,et al.  Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine Is a Relatively Selective CYP3A4 Inhibitor , 2008, Drug Metabolism and Disposition.

[86]  G. Zhai,et al.  In vivo evaluation of curcumin loaded nanosuspensions by oral administration. , 2012, Journal of biomedical nanotechnology.

[87]  B. Aggarwal,et al.  Curcumin Derived from Turmeric ( Curcuma longa ): a Spice for All Seasons , 2005 .

[88]  Thorsteinn Loftsson,et al.  Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. , 2002, International journal of pharmaceutics.

[89]  Han‐Gon Choi,et al.  Enhanced oral bioavailability of curcumin via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique. , 2011, Biological & pharmaceutical bulletin.

[90]  A. Bansal,et al.  Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[91]  Makoto Takahashi,et al.  Evaluation of an oral carrier system in rats: bioavailability and antioxidant properties of liposome-encapsulated curcumin. , 2009, Journal of agricultural and food chemistry.

[92]  Zhang-bao Chen,et al.  Silica-coated flexible liposomes as a nanohybrid delivery system for enhanced oral bioavailability of curcumin , 2012, International journal of nanomedicine.

[93]  Yun-Jin Jung,et al.  Curcumin is an inhibitor of p300 histone acetylatransferase. , 2006, Medicinal chemistry (Shariqah (United Arab Emirates)).

[94]  S. Suresh,et al.  Effect of Cyclodextrin Complexation of Curcumin on its Solubility and Antiangiogenic and Anti-inflammatory Activity in Rat Colitis Model , 2009, AAPS PharmSciTech.

[95]  H. Lou,et al.  Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. , 2006, Journal of pharmaceutical and biomedical analysis.

[96]  I. Villegas,et al.  New mechanisms and therapeutic potential of curcumin for colorectal cancer. , 2008, Molecular nutrition & food research.

[97]  K. N. Babu,et al.  Turmeric: The genus Curcuma , 2007 .

[98]  Jen-kun Lin,et al.  Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. , 1996, Biochimica et biophysica acta.

[99]  R. Peters.  Professor Dr Chem. Barend Coenraad Petrus Jansen (1 April 1884-18 October 1962) , 1964, British Journal of Nutrition.

[100]  D. K. Maity,et al.  Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. , 2003, Free radical biology & medicine.

[101]  O. P. Sharma.  Antioxidant activity of curcumin and related compounds. , 1976, Biochemical pharmacology.

[102]  R. Kurzrock,et al.  Evaluation of liposomal curcumin cytochrome p450 metabolism. , 2010, Anticancer research.

[103]  Ying Chen,et al.  Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment. , 2008, Biological & pharmaceutical bulletin.

[104]  M. Pirmohamed,et al.  Phase I Clinical Trial of Oral Curcumin , 2004, Clinical Cancer Research.

[105]  B. Aggarwal,et al.  Anticancer potential of curcumin: preclinical and clinical studies. , 2003, Anticancer research.

[106]  P. Negi,et al.  Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture. , 1999, Journal of agricultural and food chemistry.

[107]  T. Osawa,et al.  Involvement of the beta-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin. , 1996, Biochemical pharmacology.

[108]  H. Ammon,et al.  Pharmacology of Curcuma longa , 1991, Planta medica.

[109]  M. Ramírez-Silva,et al.  Determination of acidity constants of curcumin in aqueous solution and apparent rate constant of its decomposition. , 2004, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.