MaxHealth Labs Curcumin Clinical Study | goldentigerlipids.com
Curcumin Clinical Study
BioAvailability & Absorption of Oral Curcumin Cu (ll)
This study has been completed.
Sponsor: Xyrion Medical, Inc.
Collaborators: Xyrion Medical, Inc.
Information provided by:
Clinical Study Number: CUR001-1113
First received: Nov 16, 2013
Last updated: NA
Last verified: Nov 16, 2013
Locations: Miami, FL
Sponsors and Collaborators: Xyrion Medical, Inc.
Official Title: In Vivo Clinical Study of the BioAvailability & Absorption of Plasma Curcumin
Glucuronide Concentrations in Rats Using Oral Intra-Cellular Curcumin Cu (ll).
Controlled Trial of Plasma Concentrations
Allocation: Controlled Trial of Plasma Concentrations
Testing Method: High-pressure liquid chromatography (HPLC) with electrochemical (EC) detection
Internal Standard: 50 ul 4-hydroxybenzophenonone & 300 ul acetonitrole
STD Value: 0-350 ng/ml Endpoint Classification: Plasma Bio-Availability Study Clinical Trial Model: Pilot Study Masking: Timed Plasma Concentration Study Primary Purpose: Basic Science and Research
Primary Outcome Measures:
· Plasma Curcumin and Curcumin Glucuronide Concentrations [Time Frame: 10, 20, 30, and 40 mins]
· Number of rats used: 15
· Study Start Date: November 16, 2013
· Primary Completion Date: November 16, 2013
Introduction & Purpose:
Wide arrays of phenolic substances, especially those present in dietary and medicinal plants, have been reported to possess substantial antioxidant, anti-inflammatory, anticarcinogenic, and antimutagenic effects (1-3). The spice curcumin is used in curries as a coloring and flavoring agent in various parts of the world, especially in the Indian subcontinent, an area that has a low incidence of colorectal cancer (4).
Curcumin is a yellow pigment found in turmeric (Curcuma Longa L.), and is reported, in recent studies, to have several pharmacological effects, including anti-oxidant, anti-inflammatory, anti-tumor and lipid-lowering properties. However, as most curcumin is conjugated when absorbed through the intestine, free curcumin is present at extremely low levels inside the body. Therefore, curcumin metabolites have been presumed to be responsible for the curcumin bioactivity. It has been confirmed that curcumin glucuronide is the major metabolite of curcumin found in the plasma after oral administration of curcumin in rats.
Animal model studies (several) have shown that curcumin suppresses carcinogenesis in skin (5- 7), stomach (8, 9), colon (10, 11), breast (12-14), and liver (15). Curcumin is reported to induce apoptosis in a wide variety of tumor cells, including B- and T-cell leukemias (16, 17), colon (18), and breast carcinoma (19, 20). Chemopreventive activities of curcumin are thought to involve up-regulation of carcinogen-detoxifying enzymes (21-23) and antioxidants (24, 25), suppression of cyclooxygense-2 expression (26-30), and inhibition of nuclear factor-κB release (30-32). Inhibition of nuclear factor-κB release by curcumin also leads to the down-regulation of various proinflammatory cytokines (e.g., tumor necrosis factor and interleukins) and inhibition of the mRNA expression of several proinflammatory enzymes (e.g., cyclooxygense, lipoxygenases, metalloproteinases, and nitric oxide synthase; ref. (33).
In animal studies, curcumin undergoes rapid metabolic reduction and conjugation, resulting in poor systemic bioavailability after oral administration (34-36). IE:An oral dose of 0.1 g/kg administered to mice yielded a peak plasma concentration of free curcumin that was only 2.25 μg/mL (35). In rats, curcumin completely disappeared from plasma within 1/2 h after a 40 mg/kg i.v. dose (34). When given orally at a 500 mg/kg dose, peak concentrations of 1.8 ng/mL of free curcumin were detected in plasma (34). The major metabolites of curcumin identified in rat plasma were curcumin glucuronide and curcumin sulfate based on enzymatic hydrolysis studies. (34).
In animal models, no toxicity has been reported to date. Similarly, in humans to date, few adverse events due to curcumin have been reported---even at high doses (35). In this study, a single dose of curcumin resulted in rapid appearance of the curcumin conjugate glucoronide in rat plasma.
Bioavailability & Absorption:
The reasons for reduced bioavailability of any agent within the body are low intrinsic activity, poor absorption, high rate of metabolism, inactivity of metabolic products and/or rapid elimination and clearance from the body. Studies to date have suggested a strong intrinsic activity and, hence, efficacy of curcumin as a therapeutic agent for various ailments. However, studies over the past three decades related to absorption, distribution, metabolism, and excretion of curcumin have revealed poor absorption and rapid metabolism of curcumin that severely curtains its bioavailability. Serum Concentration. One of the major observations related to curcumin studies involves the observation of extremely low serum levels. The ﬁrst reported study to examine the uptake, distribution, and excretion of curcumin was by Wahlstrom and Blennow in 1978 using Sprague– Dawley rats. Negligible amounts of curcumin in blood plasma of rats after oral administration of 1 g/kg of curcumin showed that curcumin was poorly absorbed from the gut.
Various studies have evaluated the metabolism of curcumin in rodents and in humans. Once absorbed, curcumin is subjected to conjugations like sulfation and glucuronidation at various tissue sites. The very first biodistribution study reported the metabolism of major part of curcumin orally administered to rats. (36) Liver was indicated as the major organ responsible for metabolism of curcumin. (35, 37, 38). Holder et al. reported that the major billiary metabolites of\ curcumin are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) in rats. A minor biliary metabolite was dihydroferulic acid together with traces of ferulic acid. (39) In addition to glucuronides, sulfate conjugates were found in the urine of curcumin treated rats. (40) Hydrolysis of plasma samples with glucuronidase by Pan et al. showed that 99% of curcumin in plasma was present as glucuronide conjugates. This study also revealed curcumin–glucuronoside, dihydrocurcumin–glucuronoside, tetrahydrocurcumin (THC)–glucuronoside, and THC are major metabolites of curcumin in vivo. (41) These results are in agreement with Ireson et al. who examined curcumin metabolites in rat and human. (42) Asai et al. evaluated the absorption and metabolism of orally administered curcumin in rats. The enzymatic hydrolysis of plasma samples showed that the predominant metabolites in plasma following oral administration were glucuronides/sulfates of curcumin. The plasma concentrations of conjugated curcuminoids reached a maximum 1 h after administration. The presence of conjugative enzyme activities for glucuronidation and sulfation of curcumin in liver, kidney and intestinal mucosa suggested that orally administered curcumin is absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide/sulfate conjugates. (43) Curcumin sulfate and curcumin glucuronide were identified in the colorectal tissue of colorectal cancer patients who ingested curcumin capsules. (37) Hoehle and co-workers examined the metabolism of curcumin by rat liver tissue slices and showed the formation of reductive metabolites as THC, HHC, and octahydrocurcumin (OHC); males had more OHC, whereas females had more THC metabolites. (38) Further, the same group showed substantial contribution of gastrointestinal tract in glucuronidation of curcumin in humans, which may have important implications for their pharmacokinetic fate in vivo. (44) Thus, curcumin undergoes extensive reduction, most likely through alcohol dehdrogenase, followed by conjugation.
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. The pharmacological safety and efficacy of curcumin makes it a potential compound for treatment and prevention of a wide variety of human diseases. In spite of its efficacy and safety, curcumin has not yet been approved as a therapeutic agent and the relative bioavailability of curumin has been highlighted as a major problem for this. The purpose of this review is to discuss the means of improving the bioavailability of curcumin and curumin metabolites. There are studies which suggest that curcumin glucuronides may actually be more active than curcumin. (45-50).
The absorption, biodistribution, metabolism, and elimination studies of curcumin have, unfortunately, shown only poor absorption, rapid metabolism, and elimination of curcumin as major reasons for poor bioavailability of this interesting polyphenolic compound. Some of the possible ways to overcome these problems are discussed below. Nanoparticles, liposomes, micelles, and phospholipid complexes are promising novel formulations, which appear to provide longer circulation, better permeability, and resistance to metabolic processes.
Liposomes are excellent drug delivery systems since they can carry both hydrophilic and hydrophobic molecules. Liposomes are artificially-prepared vesicle composed of a lipid bilayer. The liposome can be used as a vehicle for administration of nutrients and pharmaceutical drugs depending upon the need. A liposome encapsulates a region of aqueous solution inside a hydrophobic membrane; dissolved hydrophilic solutes cannot readily pass through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way liposome can carry both hydrophobic molecules and hydrophilic molecules. To deliver the molecules to sites of action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus delivering the liposome content. Li et al. investigated the in Vitro and in ViVo antitumor activity of liposomal curcumin against human pancreatic carcinoma cells and demonstrated that liposomal curcumin inhibits pancreatic carcinoma growth and, in addition, exhibits antiangiogenic effects. Liposomal curcumin suppressed the pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. The preclinical anticancer activity of a liposomal curcumin formulation in colorectal cancer was also recently evaluated. This study also compared the efficacy of liposomal curcumin with that of oxaliplatin, a standard chemotherapeutic agent for colorectal cancer. There was synergism between liposomal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in vitro. In vivo, significant tumor growth inhibition was observed in Colo205 and LoVo xenografts, and the growth inhibition by liposomal curcumin was greater than that for oxaliplatin in Colo205 cells. Thus, this study established the comparable or greater growth-inhibitory and apoptotic effects of liposomal curcumin with oxaliplatin both in vitro and in vivo in colorectal cancer (51). Ruby et al. also reported the antitumor and antioxidant activities of neutral unilamellar liposomal curcuminoids in mice.3 Nevertheless, in ViVo preclinical studies are warranted to show the increased bioavailability of liposomal curcumin over free curcumin. Kanwar et al. evaluated the in Vitro cellular uptake of liposomal and albumin loaded curcumin. From these studies it was found that liposomal vehicle is capable of loading more curcumin in to cells than either HSA or aqueous-DMSO, and lymphoma cells showed preferential uptake of curcumin to lymphocytes (51)
Method & Analysis:
15 rats were orally fed approx 1 ml of Intra-Cellular Liposomal Curcumin Cu (ll) at 150 mg/5ml (IE: 30 mg of Intra-Cellular Curcumin Cu (ll). Blood samples were taken at the indicated times and collected into heparin treated micro-centrifuge tubes. The tubes were then centrifuged at 10,000 X g for 10 minutes to separate the plasma. The indicated amount of clear plasma was then removed by pipette and placed into a clean centrifuge tube. Then 50 ul of internal standard (4-hydroxy benzophenone) was added along with 300 ul of acetonitrile to precipitate proteins. The tubes were then vortexed for 20 sec and centrifuged at 10,000 X g for 10 minutes. The supernatant was then removed and placed into a HPLC auto-sampler vial and analyzed for curcumin content.
The available high co/ncentrations of curcumin glucoronide still at 40 mins very much suggests that this liposomal curcumin has the ability to remain circulating within plasma much longer than any other oral curcumin previously tested for plasma concentrations of glucoronide. The present study suggests that Liposomal Intra-Cellular Curcumin Cu11 was rapidly biotransformed at anatomic sites (potentially gastric mucosa, liver, or both) before peripheral plasma concentrations are available. It is interesting and very worthy to note that the metabolite cucrumin glucuronide actually increased slightly from the 10 to 20 minute sample, thus showing a slight escalation even after the initial 10 minute peak.
These findings should have an implication for the future research of oral curcumin delivered via liposomal encapsulation. With the known favorable pharmacokinetic properties of curcumin and the metabolite curcumin glucoronides, it is logical to shift the current research scenario of curcumin to curcumin carriers with enhanced forms of bioavailability such as liposomal curcumin. This study for the first time, has shown significant concentrations of this metabolite (curcumin glucuronide) that previously has been absent almost immediately from systemic circulation after oral administration. Therefore, further characterization of the pharmacokinetics and pharmacodynamics of this curcumin (Intra-Cellular Curcumin Cu (ll) should be performed as a potential means of overcoming the pharmacological barriers of curcumin that are well known.
*Prior study referenced in Graph:
A simple RP‐HPLC method for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate, in rat plasma and the application to pharmacokinetic study: Ying‐Rui Hana,b, Jin‐Jin Zhua,c, Yu‐Rong Wangb, Xing‐Sheng Wangc and Yong‐Hong Liaoa---- Biomed. Chromatogr. 2011; 25: 1144–1149
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