Stereospecific pharmacokinetic characterization of liquiritigenin in the rat

Samaa Alrushaid, Neal M. Davies, Stephanie E. Martinez, Casey L. Sayre


Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague-Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection. Serum concentrations were quantified but rapidly fell to undetectable levels. S-liquiritigenin showed a short half-life (0.25-0.54 h), while a better estimation of half-life (26-77 h) and other pharmacokinetic parameters was observed using urinary data. The flavonoid is predominantly excreted via non-renal routes (fe values of 0.16-3.46 %), and undergoes rapid and extensive phase II metabolism. Chiral differences in the chemical structure of the compound result in some pharmacokinetic differences. Serum concentrations rapidly declined, making modeling difficult. S-liquiritigenin showed an increased urinary half-life.


Liquiritigenin; Pharmacokinetics; Stereospecific; Flavonoid; Chiral

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Haslam E. Practical polyphenolics: from structure to molecular recognition and physiological action. United Kingdome: Cambridge University Press; 1998. P. 422..

Cook NC, Samman S. Flavonoids-Chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem. 1996;7(2):66-76.

Bhagwat S, Haytowitz DB, Holden JM. Nutrient data laboratory. Beltsville human nutrition research center. Agricultural research service. U.S. Department of Agriculture. USDA database for the flavonoid content of selected foods. Release 3.1. 2013. Available from:

Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. Quantitation of flavonoid constituents in citrus fruits. J Agric Food Chem. 1999;47(9):3565-3571.

Nielsen SE, Freese R, Kleemola P, Mutanen M. Flavonoids in human urine as biomarkers for intake of fruits and vegetables. Cancer Epidemiol Biomarkers Prev. 2002;11(5):459-66.

Bugianesi R, Catasta G, Spigno P, D’Uva A, Maiani G. Naringenin from cooked tomato paste is bioavailable in men. J Nutr. 2002;132(11):3349-3352.

Le Gall G, DuPont MS, Mellon FA, Davis AL, Collins GJ, Verhoeyen ME, et al. Characterization and content of flavonoid glycosides in genetically modified tomato (Lycopersicon esculentum) fruits. J Agric Food Chem. 2003;51(9):2438-2446.

Stewart AJ, Bozonnet S, Mullen W, Jenkins GI, Lean ME, Crozier A. Occurrence of flavonols in tomatoes and tomato-based products. J Agric Food Chem. 2000;48(7):2663-2669.

Daigle DJ, Conkerton EJ, Sanders TH, Mixon AC. Peanut hull flavonoids: their relationship with peanut maturity. J Agric Food Chem. 1988;36(6):1179-1181.

Manach C, Morand C, Gil-Izquierdo A, Bouteloup-Demange C, Rémésy C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur J Clin Nutr. 2003;57(2):235-42.

Krause M, Galensa R. Analysis of enantiomeric flavanones in plant extracts by high-performance liquid chromatography on a cellulose triacetate based chiral stationary phase. Chromatographia. 1991;32(1):69-72.

Sayre CL, Davies NM. Quantification of three chiral flavonoids with reported bioactivity in selected licensed Canadian natural health products and US marketed dietary supplements. J Pharm Pharm Sci. 2013;16(2):272-8.

Corradini C, Borromei C, Cavazza A, Merusi C, De Rossi A, Nicoletti I. Determination of flavanones in citrus byproducts and nutraceutical products by a validated RP-HPLC method. J Liq Chromatogr Relat Technol. 2009;32(10):1448-1462.

Espin JC, Garcia-Conesa MT, Tomas-Barberan FA. Nutraceuticals: facts and fiction. Phytochemistry. 2007;68(22-24):2986-3008.

Yáñez JA, Andrews PK, Davies NM. Methods of analysis and separation of chiral flavonoids. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;848(2):159-81.

Sayre CL, Hopkins M, Takemoto JK, Davies NM. Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study. Biomed Chromatogr. 2013;27(3):404-406.

Gan P, Huang X, Zhong M, Sun M, Qin F, Zhang C. Simultaneous determination of eight major constituents in the traditional Chinese medicine Shaoyao-Gancao-Tang by UPLC-PDA. J Med Plants Res. 2010;4(24):2615-2621.

Yan Y, Chai C-Z, Wang D-W, Wu J, Xiao HH, Huo LX, et al. Simultaneous determination of puerarin, daidzin, daidzein, paeoniflorin, albiflorin, liquiritin and liquiritigenin in rat plasma and its application to a pharmacokinetic study of Ge-Gen Decoction by a liquid chromatography-electrospray ionization-tandem m. J Pharm Biomed Anal. 2014;95:76-84.

Qiao X, Ye M, Xiang C, Wang Q, Liu CF, Miao WJ, et al. Analytical strategy to reveal the in vivo process of multi-component herbal medicine: a pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry. J Chromatogr A. 2012;1258:84-93.

Shimamura H, Suzuki H, Hanano M, Suzuki A, Sugiyama Y. Identification of tissues responsible for the conjugative metabolism of liquiritigenin in rats: an analysis based on metabolite kinetics. Biol Pharm Bull. 1993;16(9):899-907.

Li T, Yan Z, Zhou C, Sun J, Jiang C, Yang X. Simultaneous quantification of paeoniflorin, nobiletin, tangeretin, liquiritigenin, isoliquiritigenin, liquiritin and formononetin from Si-Ni-San extract in rat plasma and tissues by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2013;27(8):1041-1053.

Kang HE, Sohn SI, Baek SR, Lee JW, Lee MG. Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats. J Pharm Pharmacol. 2011;63(1):49-57.

Kang HE, Sohn SI, Baek SR, Lee JW, Lee MG. Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5’-diphosphoglucuronic acid level. Metabolism. 2010;59(10):1472-1780.

Kang HE, Chung HJ, Kim HS, Lee JW, Lee MG. Pharmacokinetic interaction between liquiritigenin (LQ) and DDB: increased glucuronidation of LQ in the liver possibly due to increased hepatic blood flow rate by DDB. Eur J Pharm Sci. 2010;39(1–3):181-189.

Kang HE, Cho YK, Jung HY, Choi KY, Sohn SI, Baek SR, et al. Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect. Xenobiotica. 2009;39(6):465-475.

Kang HE, Jung HY, Cho YK, Kim SH, Sohn SI, Baek SR, et al. Pharmacokinetics of liquiritigenin in mice, rats, rabbits, and dogs, and animal scale-up. J Pharm Sci. 2009;98(11):4327-4342.

Kamei J, Saitoh A, Asano T, Nakamura R, Ichiki H, Iiduka A, et al. Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of Glycyrrhizae radix (licorice), a main component of the Kampo preparation Bakumondo-to (Mai-men-dong-tang). Eur J Pharmacol. 2005;507(1-3):163-168.

Li C, Homma M, Oka K. Characteristics of delayed excretion of flavonoids in human urine after administration of Shosaiko-to, a herbal medicine. Biol Pharm Bull. 1998;21(12):1251–-1257.

Yang CY, Tsai SY, Chao PDL, Yen HF, Chien TM, Hsiu SL. Determination of hesperetin and its conjugate metabolites in serum and urine. J Food Drug Anal. 2002;10(3):143-148.

Kang HE, Cho YK, Jung HY, Choi KY, Sohn SI, Baek SR, et al. Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect. Xenobiotica. 2009;39(6):465-475.

Remsberg CM, Yáñez JA, Ohgami Y, Vega-Villa KR, Rimando AM, Davies NM. Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity. Phytother Res. 2008;22(2):169-179.

Roupe KA, Yáñez JA, Teng XW, Davies NM. Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats. J Pharm Pharmacol. 2006;58(11):1443-1450.

Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093-10955.


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