PDF herunterladen
Drug Res (Stuttg) 2013; 63(12): 620-624
DOI: 10.1055/s-0033-1349837
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Comparison of the Exposure of Glycyrrhizin and its Metabolites and the Pseudoaldosteronism after Intravenous Administration of Alpha- and Beta-glycyrrhizin in Rat

R. Xu
1   Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
,
Q. Xiao
1   Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
,
Y. Cao
1   Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
,
J. Yang
1   Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 06. April 2013

accepted 18. Juni 2013

Publikationsdatum:
17. Juli 2013 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Glycyrrhizin, the major bioactive component in licorice root extract, exists as 2 isomers, α and β-glycyrrhizin, and is associated with causing pseudoaldosteronism due to its principal metabolites, glycyrrhetinic acid and 3-monoglucuronyl-glycyrrhetinic acid. The aim of this study was to compare (a) the pharmacokinetics of glycyrrhizin and its metabolites in rat after the first and last intravenous doses of either α- or β-glycyrrhizin administered once a day over 6 days, (b) kidney levels of the metabolites at 24 h after the last dose and (c) the urinary cortisol:cortisone ratio (as a biomarker of pseudoaldosteronism) in total urine collected for 24 h after the last dose.

After the first dose, the clearance of glycyrrhizin in rats given α-isomer was significantly higher than in those given β-isomer and the AUC0–24 h values of glycyrrhizin and the metabolites were all significantly higher in β group than in α group. After the last dose, the AUC0–24 h values of glycyrrhizin and its metabolites were again significantly higher in rats given β-isomer than those given α-isomer and were all higher than the corresponding values after the first dose. Moreover, only kidney levels of glycyrrhetinic acid were detected in β group. The urinary cortisol:cortisone ratio was higher in rats given β-isomer and the correlation coefficients of the ratios with the AUC0–24 h values of 2 metabolites were 0.81 and 0.89 respectively.

The results of the present study indicate that α-glycyrrhizin is a safer drug than β- glycyrrhizin probably due to a lower systemic exposure to the 2 metabolites.

Key words

glycyrrhetinic acid - 3-monoglucuronyl-­glycyrrhetinic acid - isomer - systemic exposure - pseudoaldosteronism
 

  • References

  • 1 Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 2008; 22: 709-724
    CrossrefPubMedGoogle Scholar
  • 2 Koga K, Ohmachi K, Kawashima S et al. Determination of 18alpha-glycyrrhizin and 18beta-glycyrrhizin in dog plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 2000; 738: 165-168
    CrossrefPubMedGoogle Scholar
  • 3 Sun L, Shen J, Pang X et al. Phase I safety and pharmacokinetic study of magnesium isoglycyrrhizinate after single and multiple intravenous doses in chinese healthy volunteers. J Clin Pharmacol 2007; 47: 767-773
    CrossrefPubMedGoogle Scholar
  • 4 Qu Y, Chen WH, Zong L et al. 18alpha-Glycyrrhizin induces apoptosis and suppresses activation of rat hepatic stellate cells. Med Sci Monit 2012; 18: BR24-BR32
    CrossrefPubMedGoogle Scholar
  • 5 Mao Yimin ZM, Chen Y, Chen C et al. Magnesium isoglycyrrhizinate in the treatment of chronic liver diseases: A randomized, double-blind, multi-doses, active drug controlled, multi-center study. Chinese Journal of Hepatology 2009; 17: 847-851
    PubMedGoogle Scholar
  • 6 Farese Jr RV, Biglieri EG, Shackleton CH et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991; 325: 1223-1227
    CrossrefPubMedGoogle Scholar
  • 7 Serra A, Uehlinger DE, Ferrari P et al. Glycyrrhetinic acid decreases plasma potassium concentrations in patients with anuria. J Am Soc Nephrol 2002; 13: 191-196
    PubMedGoogle Scholar
  • 8 Kato H, Kanaoka M, Yano S et al. 3-Monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin Endocrinol Metab 1995; 80: 1929-1933
    CrossrefPubMedGoogle Scholar
  • 9 Ohtake N, Kido A, Kubota K et al. A possible involvement of 3-monoglucuronyl-glycyrrhetinic acid, a metabolite of glycyrrhizin (GL), in GL-induced pseudoaldosteronism. Life Sci 2007; 80: 1545-1552
    CrossrefPubMedGoogle Scholar
  • 10 Makino T, Okajima K, Uebayashi R et al. 3-Monoglucuronyl-glycyrrhretinic acid is a substrate of organic anion transporters expressed in tubular epithelial cells and plays important roles in licorice-induced pseudoaldosteronism by inhibiting 11beta-hydroxysteroid dehydrogenase 2. J Pharmacol Exp Ther 2012; 342: 297-304
    CrossrefPubMedGoogle Scholar
  • 11 Pippal JB, Fuller PJ. Structure-function relationships in the mineralocorticoid receptor. J Mol Endocrinol 2008; 41: 405-413
    CrossrefPubMedGoogle Scholar
  • 12 Palermo M, Shackleton CH, Mantero F et al. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf) 1996; 45: 605-611
    CrossrefPubMedGoogle Scholar
  • 13 Best R, Walker BR. Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11 beta-hydroxysteroid dehydrogenase in vivo. Clin Endocrinol (Oxf) 1997; 47: 231-236
    CrossrefPubMedGoogle Scholar
  • 14 Cuzzola A, Petri A, Mazzini F et al. Application of hyphenated mass spectrometry techniques for the analysis of urinary free glucocorticoids. Rapid Commun Mass Spectrom 2009; 23: 2975-2982
    CrossrefPubMedGoogle Scholar
  • 15 Omar HR, Komarova I, El-Ghonemi M et al. Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab 2012; 3: 125-138
    CrossrefPubMedGoogle Scholar