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Clinical Safety of Licorice Flavonoid Oil (LFO) and Pharmacokinetics of Glabridin in Healthy Humans

Functional Food Ingredients Division, (F.A., S.Y., Y.T., N.A.)
Life Science Research Laboratories (M.K.), Life Science RD Center, Kaneka Corporation, Hyogo
Functional Food Ingredients Division, Kaneka Corporation, Osaka (K.N., T.M.)
Haradoi Hospital (H.I.)
Tenjin Sogo Clinic (K.N.), Fukuoka, JAPAN

Address reprint requests to: Fumiki Aoki, MSc, Functional Food Ingredients Division, Kaneka Corporation, 1–8 Miyamae-machi, Takasago-cho, Takasago, Hyogo 676-8688, JAPAN. E-mail: Fumiki.Aoki{at}kn.kaneka.co.jp

Objective: Licorice flavonoids have various physiological activities such as abdominal fat-lowering, hypoglycemic and antioxidant effects. Licorice flavonoid oil (LFO: Kaneka Glavonoid Rich Oil^TM) 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 (C_max) after approximately 4 h (T_max), and then eliminated relatively slowly in a single phase with a T_1/2 of approximately 10 h at all doses. The C_max 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.

Key words: licorice, glabridin, safety, pharmacokinetics, flavonoid, human

Abbreviations: ADME = absorption, distribution, netabolism and excretion • A/G ratio = albumin/globulin ratio • ALP = alkaline phosphatase • ALT = alanine aminotransferase • APTT = activated partial thromboplastin time • AST = aspartate aminotransferase • AUC = area under the curve • BUN = blood urea nitrogen • CL/F = total clearance • C_max = the maximum concentration in plasma • LDH = lactate dehydrogenase • LFO = licorice flavonoid oil • MCT = medium-chain triglycerides • NOAEL = no-observed-adverse-effect-level • PT = prothrombin time • T_1/2 = elimination half-life • T_max = time required to reach maximum concentration • -GTP = -glutamyltranspeptidase