In a study by Pan et al. using a mouse model, a curcumin dose of 0.1 g/kg via i.p. route showed a maximum amount of curcumin in the intestine (117 µg/ g) 1 h after dosing. Spleen, liver, and kidney showed moderate curcumin amounts of 26.1, 26.9, and 7.5 µg/g, respectively, whereas only a trace amount (0.4 µg/g) was found in brain tissue.34 In a study with C57Bl/6J mice, the animals initially received curcumin (0.2%) in their diet for 1 week and were then changed to a curcumin-free diet. Levels of curcumin in gastrointestinal and hepatic tissues were analyzed for curcumin for up to 16 days after cessation of curcumin feeding. After termination of dietary curcumin intake, tissue levels of curcumin declined rapidly to unquantifiable amounts within 3–6 h. Second, in a more general analysis, mice received [14C]curcumin (100 mg/ kg) via the i.p. route and were then monitored for the disappearance of radioactivity associated with the cur- cumin molecule. Radioactivity measured in tissues after i.p. injection of [14C]curcumin achieved the following peak levels, expressed as nmol/g of tissue: liver, 73 ( 20; intestinal mucosa, 200 ( 23; brain, 2.9 ( 0.4, heart, 9.1 ( 1.1; lungs, 16 ( 3; muscle 8.4 ( 6.0; kidney, 78 ( 3. Beyond the peak, radioactivity declined swiftly to reach levels between 20 and 33% of peak values at 4 h, or in the case of the small intestine, 8 h, after dosing.35
Similarly, the concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3600 mg of curcumin were 12.7 ( 5.7 and 7.7 ( 1.8 nmol/g, respec- tively, and these doses had pharmacological activity in colorectum as measured by effects on levels of M(1)G and COX-2 protein.41 Another study by the same group showed no curcumin in liver tissues of patients, with hepatic metastases from colorectal cancer, who received 450–3600 mg of curcumin daily for 1 week prior to surgery.42 These studies suggest that curcumin pharmacokinetics observed in tissues after i.p. administration cannot be compared directly with those observed after gavage or dietary intake. The tissue and serum distribution of curcumin reported in various animal and human studies is summarized in Table 1.
B3. Metabolites. 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.31 Liver was indicated
Garcea, G.; Jones, D. J.; Singh, R.; Dennison, A. R.; Farmer, P. B.; Sharma, R. A.; Steward, W. P.; Gescher, A. J.; Berry, D. P. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br. J. Cancer 2004, 90 (5), 1011–5.
Garcea, G.; Berry, D. P.; Jones, D. J.; Singh, R.; Dennison, A. R.; Farmer, P. B.; Sharma, R. A.; Steward, W. P.; Gescher, A. J. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol. Biomarkers. PreV. 2005, 14 (1), 120–5.
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as the major organ responsible for metabolism of curcumin.31,41,43 Holder et al. reported that the major billiary metabolites of curcumin are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) in rats. A minor biliary metabo- lite was dihydroferulic acid together with traces of ferulic acid.44 In addition to glucuronides, sulfate conjugates were found in the urine of curcumin treated rats.32 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–glucurono- side, dihydrocurcumin–glucuronoside, tetrahydrocurcumin (THC)–glucuronoside, and THC are major metabolites of curcumin in vivo.34 These results are in agreement with Ireson et al. who examined curcumin metabolites in rat and human.45 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 metabo- lized to the form of glucuronide/sulfate conjugates.46 Cur- cumin sulfate and curcumin glucuronide were identified in the colorectal tissue of colorectal cancer patients who ingested curcumin capsules.41 Hoehle and co-workers ex- amined 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.43 Further, the same group showed substantial contribution of gastrointes- tinal tract in glucuronidation of curcumin in humans, which may have important implications for their pharmacokinetic fate in vivo.47 Thus, curcumin undergoes extensive reduction, most likely through alcohol dehdrogenase, followed by conjugation. Curcumin and its metabolites are schematically shown in Figure 1.
Hoehle, S. I.; Pfeiffer, E.; Solyom, A. M.; Metzler, M. Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. J. Agric. Food Chem. 2006, 54 (3), 756–64.
Holder, G. M.; Plummer, J. L.; Ryan, A. J. The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione) in the rat. Xenobiotica 1978, 8 (12), 761–
Ireson, C.; Orr, S.; Jones, D. J.; Verschoyle, R.; Lim, C. K.; Luo,
L.; Howells, L.; Plummer, S.; Jukes, R.; Williams, M.; Steward,
P.; Gescher, A. Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res. 2001, 61 (3), 1058–64.
Asai, A.; Miyazawa, T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci. 2000, 67 (23), 2785–93.