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BioaVailability of Curcumin: Problems and Promises

Whether curcumin metabolites are as active as curcumin itself is, unfortunately, not clear. While most studies indicate that curcumin glucuronides and THC are less active than curcumin itself,45,48 there are other studies which suggest that they may actually be more active than curcumin.4,49–54 For example, THC was found to show better antidiabetic and antioxidant activity than curcumin in type 2 diabetic rats,54 whereas Sandur et al. established much lower anti- inflammatory and antiproliferative activities of THC com- pared to curcumin.48 Further, a study by Ireson et al. established that the metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression,45 indicating lesser antiproliferative effects of curcumin metabolites like glucuronides and THC than curcumin. The phenolic glucuronide of curcumin and of its natural congeners, but not the parent compounds, inhibited the assembly of microtubule proteins under cell- free conditions, implying chemical reactivity of the glucu- ronides.49 The difference in results is most likely due to the nature of the assays employed. The lack of availability of curcumin glucuronides and related compounds contributes to a continued lack of clear understanding of the relative pharmacologic activities of observed curucmin metabolites.

B4. Half-Life. Systemic elimination or clearance of cur- cumin from the body is also an important factor, which determines its relative biological activity. An early study by Wahlstrom and Blennow reported that when 1 g/kg curcumin

(47) Hoehle, S. I.; Pfeiffer, E.; Metzler, M. Glucuronidation of curcuminoids by human microsomal and recombinant UDP- glucuronosyltransferases. Mol. Nutr. Food Res. 2007, 51 (8), 932– 938.

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    Sandur, S. K.; Pandey, M. K.; Sung, B.; Ahn, K. S.; Murakami,

    • A.

      ; Sethi, G.; Limtrakul, P.; Badmaev, V.; Aggarwal, B. B. Curcumin, Demethoxycurcumin, Bisdemothoxycurcumin, Tet- rahydrocurcumin, and Turmerones Differentially Regulate Anti- inflammatory and Antiproliferative Responses Through a ROS- Independent Mechanism. Carcinogenesis 2007.

  • (49)

    Pfeiffer, E.; Hoehle, S. I.; Walch, S. G.; Riess, A.; Solyom, A. M.; Metzler, M. Curcuminoids form reactive glucuronides in vitro. J. Agric. Food Chem. 2007, 55 (2), 538–44.

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    Kim, J. M.; Araki, S; Kim, D. J.; Park, C. B.; Takasuka, N.; Baba- Toriyama, H.; Ota, T.; Nir, Z.; Khachik, F.; Shimidzu, N.; Tanaka,

    • Y.

      ; Osawa, T.; Uraji, T.; Murakoshi, M.; Nishino, H.; Tsuda, H. Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Car- cinogenesis 1998, 19 (1), 81–5.

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    Okada, K.; Wangpoengtrakul, C.; Tanaka, T.; Toyokuni, S.; Uchida, K.; Osawa, T. Curcumin and especially tetrahydrocur- cumin ameliorate oxidative stress-induced renal injury in mice.

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      Nutr. 2001, 131 (8), 2090–5.

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    Naito, M.; Wu, X.; Nomura, H.; Kodama, M.; Kato, Y.; Osawa,

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      The protective effects of tetrahydrocurcumin on oxidative stress in cholesterol-fed rabbits. J. Atheroscler. Thromb. 2002, 9 (5), 243–50.

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    Pari, L.; Amali, D. R. Protective role of tetrahydrocurcumin (THC) an active principle of turmeric on chloroquine induced hepato- toxicity in rats. J. Pharm. Pharm. Sci. 2005, 8 (1), 115–23.

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    Murugan, P; Pari, L. Effect of tetrahydrocurcumin on plasma antioxidants in streptozotocin–nicotinamide experimental diabetes.

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      Basic Clin. Physiol. Pharmacol. 2006, 17 (4), 231–44.

reviews

was given orally to rats, 75% of it was excreted in the feces and negligible amounts were found in the urine. Intravenous (i.v.) and i.p. administration of curcumin resulted in biliary excretion of drug from cannulated rats.44 Another study using radiolabeled curcumin showed that when drug was admin- istered orally to rats at a dose of 400 mg/rat, nearly 40% of curcumin in unchanged form was found in the feces. Though no detectable amount of curcumin was found in urine, some of the derivatives like curcumin glucuronide and sulfates were observed. The major route of elimination of the radio labeled products was through feces; urinary excretion of the label was very low regardless of the dose. At lower doses of 80 mg and 10 mg of [3H]curcumin, most of the label was excreted within 72 h, while with 400 mg, considerable amounts of the label was present in tissues 12 days after dosing.33 A clinical study with 15 patients and oral curcumin doses between 36 and 180 mg of curcumin daily for up to 4 months found neither curcumin nor its metabolites in urine, but curcumin was recovered from feces.55 The absorption and elimination half-lives of orally administered curcumin (2 g/kg) in rats were reported to be 0.31 ( 0.07 and 1.7 ( 0.5 h, respectively. But in humans, the same dose of curcumin did not allow the calculation of these half-life values because the serum curcumin levels were below the detection limit at most of the time points in most of the experimental subjects.28 A lower curcumin dose of 1 g/kg administered orally in rats was found to have an elimination half-life value of 1.45 h,38 which is not significantly different from the half-life reported for a higher curcumin dose and may be indicative of dose independency of curcumin elimination half-life in rats. The elimination half-life values for i.v. (10 mg/kg) and oral (500 mg/kg) curcumin in rats were reported to be 28.1 ( 5.6 and 44.5 ( 7.5 h, respectively.37 However, the existing evidence in literature is not enough to conclude about the factors controlling in vivo elimination half-life of curcumin and future studies are warranted to address this issue.

C. Promises

The absorption, biodistribution, metabolism, and elimina- tion 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. Adjuvants, which can block metabolic pathways of curcumin, are one of the major means that are being used to improve its bioavailability. Nanoparticles, liposomes, micelles, and phospholipid complexes are other promising novel formula- tions, which appear to provide longer circulation, better permeability, and resistance to metabolic processes.

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    Sharma, R. A.; McLelland, H. R.; Hill, K. A.; Ireson, C. R.; Euden,

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      A.; Manson, M. M.; Pirmohamed, M; Marnett, L. J.; Gescher,

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      J.; Steward, W. P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 2001, 7 (7), 1894–900.

VOL. 4, NO. 6 MOLECULAR PHARMACEUTICS 813

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