Numerous Studies Prove That Standard Curcumin Extracts Are Poorly Absorbed.

Enhansa Has Been Shown to be 7 - 8 More Absorbed Than Standard Curcumin Extracts

Studies Showing Low Absorption of Curcumin

No studies were found that showed even modest absorption of Curcumin.

Dose escalation of a curcuminoid formulation.

Lao CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE.

Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, 2150 CCGC, Ann Arbor, MI 48109-0930, USA. clao@umich.edu

BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related.

No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.

1: Br J Cancer. 2004 Mar 8;90(5):1011-5.

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration.

Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, Steward WP, Gescher AJ, Berry DP.

Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Biochemistry, University of Leicester, 5th Floor Robert Kilpatrick Clinical Sciences Building, Leicester LE2 7LX, UK. gg43@le.ac.uk

Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples.

The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.

1: Clin Cancer Res. 2008 Jul 15;14(14):4491-9.

Phase II trial of curcumin in patients with advanced pancreatic cancer.

Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R.

Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

PURPOSE: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. EXPERIMENTAL DESIGN: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. RESULTS: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. CONCLUSIONS: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

1: Mol Pharm. 2007 Nov-Dec;4(6):807-18. Epub 2007 Nov 14.

Bioavailability of curcumin: problems and promises.

Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.

Cytokine Research Laboratory and Pharmaceutical Development Center, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

1: Adv Exp Med Biol. 2007;595:453-70

Pharmacokinetics and pharmacodynamics of curcumin.

Sharma RA, Steward WP, Gescher AJ.

Radiation Oncology & Biology, University of Oxford, Churchill Hospital, UK. ricky.sharma@rob.ox.ac.uk

Curcuma spp. contain turmerin, essential oils, and curcuminoids, including curcumin. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is regarded as the most biologically active constituent of the spice turmeric and it comprises 2-8% of most turmeric preparations. Preclinical data from animal models and phase I clinical studies performed with human volunteers and patients with cancer have demonstrated low systemic bioavailability following oral dosing. Efficient first-pass metabolism and some degree of intestinal metabolism, particularly glucuronidation and sulfation of curcumin, might explain its poor systemic availability when administered via the oral route. A daily oral dose of 3.6 g of curcumin is compatible with detectable levels of the parent compound in colorectal tissue from patients with cancer. The levels demonstrated might be sufficient to exert pharmacological activity. There appears to be negligible distribution of the parent drug to hepatic tissue or other tissues beyond the gastrointestinal tract. Curcumin possesses wide-ranging anti-inflammatory and anticancer properties. Many of these biological activities can be attributed to its potent antioxidant capacity at neutral and acidic pH, its inhibition of cell signaling pathways at multiple levels, its diverse effects on cellular enzymes, and its effects on cell adhesion and angiogenesis. In particular, curcumin's ability to alter gene transcription and induce apoptosis in preclinical models advocates its potential utility in cancer chemoprevention and chemotherapy. With regard to considerable public and scientific interest in the use of phytochemicals derived from dietary components to combat or prevent human diseases, curcumin is currently a leading agent.

1: Adv Exp Med Biol. 2007;595:471-80

Clinical studies with curcumin.

Hsu CH, Cheng AL.

Department of Oncology, National Taiwan University Hospital, Taipei. chih@ha.mc.ntu.edu.tw

Curcumin has long been expected to be a therapeutic or preventive agent for several major human diseases because of its antioxidative, anti-inflammatory, and anticancerous effects. In phase I clinical studies, curcumin with doses up to 3600-8000 mg daily for 4 months did not result in discernible toxicities except mild nausea and diarrhea. The pharmacokinetic studies of curcumin indicated in general a low bioavailability of curcumin following oral application. Nevertheless, the pharmacologically active concentration of curcumin could be achieved in colorectal tissue in patients taking curcumin orally and might also be achievable in tissues such as skin and oral mucosa, which are directly exposed to the drugs applied locally or topically. The effect of curcumin was studied in patients with rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic pancreatitis, psoriasis, hyperlipidemia, and cancers. Although the preliminary results did support the efficacy of curcumin in these diseases, the data to date are all preliminary and not conclusive. It is imperative that well-designed clinical trials, supported by better formulations of curcumin or novel routes of administration, be conducted in the near future.

1: Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S139-51.

Bioavailability issues in studying the health effects of plant polyphenolic compounds.

Yang CS, Sang S, Lambert JD, Lee MJ.

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA. csyang@rci.rutgers.edu

Polyphenolic compounds are common in the diet and have been suggested to have a number of beneficial health effects including prevention of cancer, cardiovascular disease, diabetes, and others. For some dietary polyphenols, certain benficial effects are suggested by epidemiological studies, some are supported by studies in animal models, and still others are extrapolated from studies in vitro. Because of the relatively poor bioavailability of many of these compounds, the molecular basis of these beneficial effects is not clear. In the present review, we discuss the potential health benefits of dietary polyphenols from the point of view of bioavailability. Tea catechins, curcumin, and proanthocyanidins are used as examples to illustrate some of the problems that need to be resolved. Further research on both the biological activity and bioavailability of dietary polyphenols is needed to properly assess their usefulness for the prevention and treatment of disease.