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hypoglycemic,18–21 and antirheumatic22 effects of curcumin are also well established. Various animal models23,24 or human studies25–28 proved that curcumin is extremely safe even at very high doses. For example, three different phase I clinical trials indicated that curcumin, when taken as high

as 12 g per day, is well tolerated.26–28

Similarly, the efficacy

of curcumin in various diseases including cancer has been well established.29 Several clinical studies dealing with the efficacy of curcumin in humans can also be cited.1,30 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,

(7) Mahady, G. B.; Pendland, S. L.; Yun, G; Lu, Z. Z. Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen. Anticancer Res. 2002, 22 (6C), 4179– 81.

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    Kim, M. K.; Choi, G. J.; Lee, H. S. Fungicidal property of Curcuma longa L. rhizome-derived curcumin against phytopatho- genic fungi in a greenhouse. J. Agric. Food Chem. 2003, 51 (6), 1578–81.

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    Reddy, R. C.; Vatsala, P. G.; Keshamouni, V. G.; Padmanaban,

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      ; Rangarajan, P. N. Curcumin for malaria therapy. Biochem. Biophys. Res. Commun. 2005, 326 (2), 472–4.

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    Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M. C. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett 1985, 29 (2), 197–202.

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    Kiso, Y.; Suzuki, Y.; Watanabe, N.; Oshima, Y.; Hikino, H. Antihepatotoxic principles of Curcuma longa rhizomes. Planta Med. 1983, 49 (3), 185–7.

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    Venkatesan, N.Curcumin attenuation of acute adriamycin myo- cardial toxicity in rats. Br. J. Pharmacol. 1998, 124 (3), 425–7.

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    Venkatesan, N.; Punithavathi, D.; Arumugam, V. Curcumin prevents adriamycin nephrotoxicity in rats. Br. J. Pharmacol. 2000, 129 (2), 231–4.

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    Srivastava, R.; Dikshit, M.; Srimal, R. C.; Dhawan, B. N. Anti- thrombotic effect of curcumin. Thromb. Res. 1985, 40 (3), 413–

7.

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    Dikshit, M.; Rastogi, L.; Shukla, R.; Srimal, R. C. Prevention of ischaemia-induced biochemical changes by curcumin & quinidine in the cat heart. Indian J. Med. Res. 1995, 101, 31–5.

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    Nirmala, C.; Puvanakrishnan, R. Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Mol. Cell. Biochem. 1996, 159 (2), 85–93.

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    Nirmala, C.; Puvanakrishnan, R. Effect of curcumin on certain lysosomal hydrolases in isoproterenol-induced myocardial inf- arction in rats. Biochem. Pharmacol. 1996, 51 (1), 47–51.

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    Srinivasan, M. Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J. Med. Sci. 1972, 26 (4), 269–70.

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    Babu, P. S.; Srinivasan, K. Influence of dietary curcumin and cholesterol on the progression of experimentally induced diabetes in albino rat. Mol. Cell. Biochem. 1995, 152 (1), 13–21.

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    Babu, P. S.; Srinivasan, K. Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats. Mol. Cell. Biochem. 1997, 166 (1–2), 169–

75.

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    Arun, N.; Nalini, N. Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods Hum. Nutr. 2002, 57 (1), 41–52.

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    Deodhar, S. D.; Sethi, R; Srimal, R. C. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian

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      Med. Res. 1980, 71, 632–4.

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and the relative bioavailability of curcumin has been highlighted as a major problem for this. The purpose of this review is to discuss in detail the bioavailability, factors controlling bioavailability, and means to improve the bio- availability of curcumin.

B. Problems of Curcumin Bioavailability

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 cur- cumin have revealed poor absorption and rapid metabolism of curcumin that severely curtails its bioavailability. In this section, problems of curcumin bioavailability such as low serum levels, limited tissue distribution, apparent rapid metabolism and short half-life are described in detail.

B1. 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.31 In 1980, Ravindranath et al. showed that after oral admin- istration of 400 mg of curcumin to rats, no curcumin was

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    Shankar, T. N.; Shantha, N. V.; Ramesh, H. P.; Murthy, I. A.; Murthy, V. S. Toxicity studies on turmeric (Curcuma longa): acute toxicity studies in rats, guineapigs & monkeys. Indian J. Exp. Biol. 1980, 18 (1), 73–5.

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    Qureshi, S; Shah, A. H.; Ageel, A. M. Toxicity studies on Alpinia galanga and Curcuma longa. Planta Med. 1992, 58 (2), 124–7.

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    Lao, C. D.; Demierre, M. F.; Sondak, V. K. Targeting events in melanoma carcinogenesis for the prevention of melanoma. Expert ReV. Anticancer Ther. 2006, 6 (11), 1559–68.

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    Lao, C. D.; Ruffin, M. T.; Normolle, D.; Heath, D. D.; Murray,

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      I.; Bailey, J. M.; Boggs, M. E.; Crowell, J; Rock, C. L.; Brenner,

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      E. Dose escalation of a curcuminoid formulation. BMC Complement Altern. Med. 2006, 6, 10.

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    Cheng, A. L.; Hsu, C. H.; Lin, J. K.; Hsu, M. M.; Ho, Y. F.; Shen, T. S.; Ko, J. Y.; Lin, J. T.; Lin, B. R.; Ming-Shiang, W; Yu, H. S.; Jee, S. H.; Chen, G. S.; Chen, T. M.; Chen, C. A.; Lai,

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      K.; Pu, Y. S.; Pan, M. H.; Wang, Y. J.; Tsai, C. C.; Hsieh,

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      Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001, 21 (4B), 2895–900.

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    Shoba, G; Joy, D; Joseph, T; Majeed, M; Rajendran, R; Srinivas,

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      S. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998, 64 (4), 353–

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    Aggarwal, B. B.; Sundaram, C; Malani, N; Ichikawa, H. Cur- cumin: the Indian solid gold. AdV. Exp. Med. Biol. 2007, 595, 1–75.

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    Hsu, C. H.; Cheng, A. L. Clinical studies with curcumin. AdV. Exp. Med. Biol. 2007, 595, 471–80.

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