C1. Adjuvants. Piperine, a known inhibitor of hepatic and intestinal glucuronidation, was combined with curcumin and administered in rats and healthy human volunteers by Shoba et al. In rats, 2 g/kg of curcumin alone produced a maximum serum curcumin level of 1.35 ( 0.23 µg/mL at 0.83 h, whereas concomitant administration of piperine (20 mg/kg) increased the serum concentration of curcumin for a short period; time to maximum peak level (Tmax) was significantly increased, while elimination half-life and clearance were significantly decreased resulting in an increase of bioavail- ability of 154%. In contrast, in humans receiving a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine, how- ever, produced 2000% increase in bioavailability.28 Thus, the effect of piperine on bioavailability of curcumin has been shown to be much greater in humans than in rats. A human volunteer trial conducted in our group also revealed the serum curcumin level enhancing effect of piperine in human volunteers as shown in Figure 2b. Six healthy adult male human volunteers took 2 g of curcumin with or without 5 mg of piperine (as bioperine) in this crossover design study. Three people were randomized to receive curcumin only, while the remaining 3 received the curcumin + piperine combination. One week following initial drug administration, volunteers were crossed over to the opposite therapies and blood samples were again obtained for evaluation. Doubling of the absorption of curcumin was found in the presence of piperine. The effect of piperine on tissue uptake of a radio labeled fluoropropyl-substituted curcumin was evaluated in mice. Brain uptake of curcumin after 2 min was increased by 48% due to coadministration of piperine relative to that with out piperine. However, the uptake in other organs was not found to be significantly improved by piperine in this study, and the authors think this observation can be explained by the poor solubility of piperine in 10% ethanolic saline (injection medium).56 The glucuronidation inhibiting effect
28 45 of piperine glucorinides by piperine increases the and the established lesser activity of curcumin will indicate that inhibition of glucuronidation may be the major mechanism by which it bioavailability of curcumin.
Some other agents that showed a synergistic effect when used in combination with curcumin in various in vitro studies look promising for further evaluation of curcumin bioavail- ability. In a clinical study published in 2006, five familial adenomatous polyposis (FAP) patients with prior colectomy received curcumin (480 mg) and quercetin (20 mg) orally three times a day. The number and size of polyps were assessed at baseline and after therapy. All five patients had a decreased polyp number as well as size from baseline after a mean of 6 months of treatment with curcumin and quercetin. The mean percent decrease in the number and size of polyps from baseline was 60.4% and 50.9%, respectively, with minimal adverse side effects. Though the authors did
(56) Ryu, E. K.; Choe, Y. S.; Lee, K. H.; Choi, Y.; Kim, B. T. Curcumin and dehydrozingerone derivatives: synthesis, radiola- beling, and evaluation for -amyloid plaque imaging. J. Med. Chem. 2006, 49 (20), 6111–9.
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not compare the combination treatment effect with the individual effect of single agents, this study throws light at least on the therapeutic value of this combination.57
The synergistic inhibitory effect of curcumin and genistein against pesticide induced cell growth of estrogen dependent breast carcinoma cell lines (MCF-7) have been studied by Verma et al. This in Vitro study showed that a combination of curcumin and genistein completely inhibited the cellular proliferation induced by individual or a mixture of pesticides and the inhibitory effect was superior to the individual effects of either curcumin or genistein.58 Curcumin uptake within rat skin after topical application of a curcumin hydrogel, with or without eugenol or terpeneol pretreatment, was evaluated in an in ViVo study. They demonstrated the effect of eugenol and terpeniol as enhancers of skin curcumin absorption with 2.2 and 2.5-fold increases of curcumin levels in skin occurring 8 h after application. Though not strictly a bioavailability study this indicates the ability of the above agents to modulate the permeability of curcumin suggesting that these agents may also be effective as adjuvants in increasing curcumin bioavailability.59 Other recent studies indicated that EGCG (epigallocatechin-3-gallate), a compo- nent green tea, could also counteract certain activities assigned to curcumin.60 Thus, overall these studies indicate that the activity of curcumin can be modulated both at the cellular levels and at the organismic level, and we can expect surprising types of regulations when different agents are used simultaneously with curcumin.
C2. Nanoparticles. Recently, targeted and triggered drug delivery systems accompanied by nanoparticle technology have emerged as prominent solutions to the bioavailability of therapeutic agents. Nanoparticle-based delivery systems will probably be suitable for highly hydrophobic agents like curcumin circumventing the pitfalls of poor aqueous solubil- ity. However, very few studies have been published citing curcumin nanoparticles. A recent study by Bisht et al. reported the synthesis, physicochemical characterization and cancer related application of a polymer-based nanoparticle of curcumin namely “nanocurcumin” with less than 100 nm size. Nanocurcumin was found to have similar in Vitro activity as that of free curcumin in pancreatic cell lines. Like
Cruz-Correa, M.; Shoskes, D. A.; Sanchez, P.; Zhao, R.; Hylind,
M.; Wexner, S. D.; Giardiello, F. M. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2006, 4 (8), 1035–8.
Verma, S. P.; Salamone, E.; Goldin, B. Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. Biochem. Biophys. Res. Commun. 1997, 233 (3), 692–
Fang, J. Y.; Hung, C. F.; Chiu, H. C.; Wang, J. J.; Chan, T. F. Efficacy and irritancy of enhancers on the in-vitro and in-vivo percutaneous absorption of curcumin. J. Pharm. Pharmacol. 2003, 55 (5), 593–601.
Balasubramanian, S.; Eckert, R. L. Green tea polyphenol and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT/enhancer-binding protein func- tion. J. Biol. Chem. 2004, 279 (23), 24007–14.