Nucro Technics

The aim of this study was to investigate the distribution of curcumin (in the form of Lipocurc™) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes. Lipocurc™ was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans. High levels of curcumin were measured in PBMCs (625.5 ng/g w.w. cell pellet or 7,297 pg/106 cells in dog and 353.7 ng/g w.w. cell pellet or 6,809 pg/106 cells in human) and in hepatocytes (414.5 ng/g w.w. cell pellet or 14,005 pg/106 cells in dog and 813.5 ng/g w.w. cell pellet or 13,780 pg/106 cells in human). Lower curcumin levels were measured in red blood cells (dog: 78.4 ng/g w.w. cell pellet or 7.2 pg/106 cells, human: 201.5 ng/g w.w. cell pellet or 18.6 pg/106 cells). A decrease in the medium concentration of curcumin was observed in red blood cells and hepatocytes, but not in PBMCs. Red blood cell levels of THC were ~5-fold higher in dog compared to human and similar between dog and human for hepatocytes and PBMCs. The ratio of THC to curcumin found in the red blood cell medium following incubation was 6.3 for dog compared to 0.006 for human, while for PBMCs and hepatocytes the ratio of THC to curcumin in the medium did not display such marked species differences. There was an excellent correlation between the in vitro disposition of curcumin and THC following incubation with red blood cells and in vivo plasma levels of curcumin and THC in dog and human following intravenous infusion. The disposition of curcumin in blood cells is, therefore, species-dependent and of pharmacokinetic relevance.

Menaquinone-7 (MK-7) is part of a family of vitamin K that are essential co-factors for the enzyme γ-glutamyl carboxylase, which is involved in the activation of γ-carboxy glutamate (Gla) proteins in the body. Gla proteins are important for normal blood coagulation and normality of bones and arteries. The objective of this study was to examine the potential toxicity of synthetic MK-7 in BomTac:NMRI mice and in Sprague-Dawley rats. In an acute oral toxicity test, mice were administered a single oral dose of 2000 mg/kg body weight (limit dose) and no toxicity was observed during the 14-day observation period. In the subchronic oral toxicity test in rats, animals were administered MK-7 for 90 days by gavage at the following doses: 0 (vehicle control, corn oil), 2.5, 5, and 10 mg/kg body weight/day. All generated data, including clinical observations, ophthalmology, clinical pathology, gross necropsy, and histopathology, revealed no compound-related toxicity in rats. Any statistically significant findings in clinical pathology parameters and/or organ weights noted were considered to be within normal biological variability. Therefore, under the conditions of this experiment, the median lethal dose (LD50) of MK-7 after a single oral administration in mice was determined to be greater than the limit dose level of 2000 mg/kg body weight. The no observed adverse effect level (NOAEL) of MK-7, when administered orally to rats for 90 days, was considered to be equal to 10 mg/kg body weight/day, the highest dose tested, based on lack of toxicity during the 90-day study period.