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Ubiquinol is the two-electron reduction product of ubiquinone (coenzyme Q10 or CoQ10) and functions as an antioxidant in both mitochondria and lipid membranes. In humans and most mammals, including dogs, the predominant form of coenzyme Q is coenzyme Q10, whereas the primary form in rodents is coenzyme Q9 (CoQ9). Therefore, the subchronic toxicity of ubiquinol was evaluated and compared in Sprague-Dawley rats and beagle dogs. In the initial rat study, males and females were given ubiquinol at doses of 0, 300, 600, or 1200 mg/kg or ubiquinone at 1200 mg/kg by gavage for 13 weeks. This was followed by the second study, where females were given with doses of 75, 150, 200, or 300 mg/kg/day in order to determine a no observed adverse effect level (NOAEL). In the dog study, the test material was administered to males and females at dose levels of 150, 300, and 600 mg/kg, and ubiquinone was included at 600 mg/kg. Clinical observations, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, blood biochemistry, gross findings, organ weights, and histopathological findings were examined. In both species, determination of plasma and liver ubiquinol concentrations, measured as total coenzyme Q10, were performed. There were no deaths or test article-related effects in body weight, food consumption, ophthalmology, urinalysis, or hematology in rats. Histopathological examinations revealed test article-related effects on the liver, spleen, and mesenteric lymph node in female rats but not in male rats. In the liver, fine vacuolation of hepatocytes was observed in the ubiquinol groups at 200 mg/kg and above. These changes were judged to be of no toxicological significance because they were not considered to induce cytotoxic changes. Microgranuloma and focal necrosis with accumulation of macrophages were observed in the ubiquinol groups at 300 mg/kg and above. These findings were accompanied by slight increases in blood chemistry enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]), which was suggestive of either potential hepatotoxicity or a normal physiological response to ubiguinol loading. Microgranuloma, and focal necrosis were judged to be only adverse effects induced by test article based on their incidence and pathological characteristics. These changes observed in liver were thought due to uptake of the administered ubiquinol by the liver as an adaptive response to xenobiotics, and the microgranulomas and focal necrosis were considered the results of excessive uptake of ubiquinol, which exceeded the capacity for adaptive response. Based on these findings the NOAEL in rats was conservatively estimated to be 600 mg/kg/day for males and 200 mg/kg/day for females. In dogs, there were no deaths or ubiquinol-related toxicity findings during the administration period. No test article-related effects were observed in body weight, food consumption, ophthalmology, electrocardiogram, urinalysis, hematology, or blood chemistry. Histopathological examination revealed no effects attributable to administration of ubiquinol or ubiquinone in any organs examined. Based on these findings, a NOAEL for ubiquinol in male and female dogs was estimated to be more than 600 mg/kg/day under the conditions of this study. [ABSTRACT FROM AUTHOR]

Objective: Licorice flavonoids have various physiological activities such as abdominal fat-lowering, hypoglycemic and antioxidant effects. Licorice flavonoid oil (LFO: Kaneka Glavonoid Rich Oil) is a new dietary ingredient containing licorice flavonoids dissolved in medium-chain triglycerides (MCT). Glabridin is one of the bioactive flavonoids included specifically in licorice Glycyrrhiza glabra L. and is the most abundant flavonoid in LFO. In this study, we assessed the safety of LFO in healthy humans and determined the plasma concentration profile of glabridin as a marker compound.Methods: A single-dose and two multiple-dose studies at low (300 mg), moderate (600 mg) and high (1200 mg) daily doses of LFO were carried out using a placebo-controlled single-blind design. In each study the safety of LFO and the pharmacokinetics of glabridin were assessed.Results: Pharmacokinetic analysis in the single-dose study with healthy male subjects (n = 5) showed that glabridin was absorbed and reached the maximum concentration (Cmax) after approximately 4 h (Tmax), and then eliminated relatively slowly in a single phase with a T1/2 of approximately 10 h at all doses. The Cmax and AUC(0-24 h) increased almost linearly with dose. The multiple-dose studies with healthy male and female subjects for 1 week and 4 weeks suggested that plasma glabridin reached steady state levels within 2 weeks with a single daily administration of 300 to 1200 mg/day LFO. In these human studies at three dose levels, there were no clinically noteworthy changes in hematological or related biochemical parameters. All clinical events observed were mild and considered to be unrelated to LFO administration even after repeated administration for 4 weeks.Conclusion: These studies demonstrated that LFO is safe when administered once daily up to 1200 mg/day. This is the first report on the safety of licorice flavonoids in an oil preparation and the first report on the pharmacokinetics of glabridin in human subjects. [ABSTRACT FROM AUTHOR]

Abstract: The safety and bioavailability of ubiquinol (the reduced form of coenzyme Q10), a naturally occurring lipid-soluble nutrient, were evaluated for the first time in single-blind, placebo-controlled studies with healthy subjects after administration of a single oral dose of 150 or 300mg and after oral administration of 90, 150, or 300mg for 4 weeks. No clinically relevant changes in results of standard laboratory tests, physical examination, vital signs, or ECG induced by ubiquinol were observed in any dosage groups. The C max and AUC0–48h derived from the mean plasma ubiquinol concentration-time curves increased non-linearly with dose from 1.88 to 3.19μg/ml and from 74.61 to 91.76μgh/ml, respectively, after single administration. Trough concentrations had nearly plateaued at levels of 2.61μg/ml for 90mg, 3.66μg/ml for 150mg, and 6.53μg/ml for 300mg at day 14, and increased non-linearly with dose in the 4-week study. In conclusion, following single or multiple-doses of ubiquinol in healthy volunteers, significant absorption of ubiquinol from the gastrointestinal tract was observed, and no safety concerns were noted on standard laboratory tests for safety or on assessment of adverse events for doses of up to 300mg for up to 2 weeks after treatment completion. [Copyright &y& Elsevier]