THE PHARMACOKINETICS OF GLYCYRRHIZIC ACID EVALUATED BY PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING†

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. In addition, it is of clinical interest for possible treatment of chronic hepatitis C. In some highly exposed subjects, side effects such as hypertension and symptoms associated with electrolyte disturbances have been reported. To analyze the relationship between the pharmacokinetics of glycyrrhizic acid in its toxicity, the kinetics of glycyrrhizic acid and its biologically active metabolite glycyrrhetic acid were evaluated. Glycyrrhizic acid is mainly absorbed after presystemic hydrolysis as glycyrrhetic acid. Because glycyrrhetic acid is a 200–1000 times more potent inhibitor of 11-β-hydroxysteroid dehydrogenase compared to glycyrrhizic acid, the kinetics of glycyrrhetic acid are relevant in a toxicological perspective. Once absorbed, glycyrrhetic acid is transported, mainly taken up into the liver by capacity-limited carriers, where it is metabolized into glucuronide and sulfate conjugates. These conjugates are transported efficiently into the bile. After outflow of the bile into the duodenum, the conjugates are hydrolyzed to glycyrrhetic acid by commensal bacteria; glycyrrhetic acid is subsequently reabsorbed, causing a pronounced delay in the terminal plasma clearance. Physiologically based pharmacokinetic modeling indicated that, in humans, the transit rate of gastrointestinal contents through the small and large intestines predominantly determines to what extent glycyrrhetic acid conjugates will be reabsorbed. This parameter, which can be estimated noninvasively, may serve as a useful risk estimator for glycyrrhizic-acid-induced adverse effects, because in subjects with prolonged gastrointestinal transit times, glycyrrhetic acid might accumulate after repeated intake.

[1]  T. Jóhannesson,et al.  Glycyrrhetic acid in human blood after ingestion of glycyrrhizic acid in licorice. , 1997, Pharmacology & toxicology.

[2]  J. Caldwell,et al.  The formation of beta-glucuronidase resistant glucuronides by the intramolecular rearrangement of glucuronic acid conjugates at mild alkaline pH. , 1982, Biochemical pharmacology.

[3]  S. Ishida,et al.  Uptake of glycyrrhizin by isolated rat hepatocytes. , 1993, Biological & pharmaceutical bulletin.

[4]  K. Hierholzer,et al.  Inhibition of rat renal 11 beta-hydroxysteroid dehydrogenase by steroidal compounds and triterpenoids; structure/function relationship. , 1991, Biochimica et biophysica acta.

[5]  T. Kimura,et al.  Gastrointestinal absorption characteristics of glycyrrhizin from glycyrrhiza extract. , 1995, Biological & pharmaceutical bulletin.

[6]  T. Tsai,et al.  High-performance liquid chromatographic determination of 18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid in rat plasma : application to pharmacokinetic study , 1991 .

[7]  H. Kotaki,et al.  Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis , 1993, Biopharmaceutics & drug disposition.

[8]  H. Kotaki,et al.  Kinetic analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats: role of enterohepatic circulation. , 1993, Journal of pharmaceutical sciences.

[9]  H. Kotaki,et al.  Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability. , 1995, Biological & pharmaceutical bulletin.

[10]  Y. Sugiyama,et al.  Primary active transport of organic anions on bile canalicular membrane in humans. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[11]  D. Parke,et al.  The metabolism of carbenoxolone in the rat. , 1971, Xenobiotica; the fate of foreign compounds in biological systems.

[12]  K. Kobashi,et al.  Metabolism of glycyrrhizin by human intestinal flora. II. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. , 1985, Chemical & pharmaceutical bulletin.

[13]  M. Hanano,et al.  Biliary excretion and enterohepatic cycling of glycyrrhizin in rats. , 1986, Journal of pharmaceutical sciences.

[14]  R. D. de Man,et al.  Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. , 1998, Alimentary pharmacology & therapeutics.

[15]  T. Akao.  Localization of enzymes involved in metabolism of glycyrrhizin in contents of rat gastrointestinal tract. , 1997, Biological & pharmaceutical bulletin.

[16]  D. Parke,et al.  THE FATE OF TRITIUM‐LABELLED β‐GLYCYRRHETIC ACID IN THE RAT , 1963 .

[17]  Y. Akada,et al.  High-performance liquid chromatographic determination of glycyrrhizin and glycyrrhetinic acid in biological materials. , 1984, Chemical & pharmaceutical bulletin.

[18]  S. Ishida,et al.  Binding of glycyrrhetinic acid to rat plasma, rat serum albumin, human serum, and human serum albumin. , 1988, Chemical & pharmaceutical bulletin.

[19]  H. Kotaki,et al.  Selective high-performance liquid chromatographic method for the determination of glycyrrhizin and glycyrrhetic acid-3-O-glucuronide in biological fluids: application of ion-pair extraction and fluorescence labelling agent. , 1991, Journal of chromatography.

[20]  K. Kobashi,et al.  Glycyrrhizin β-D-Glucuronidase of Eubacterium sp. from Human Intestinal Flora , 1987 .

[21]  D. Meijer,et al.  Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. , 1995, Biochimica et biophysica acta.

[22]  H. Brenner,et al.  Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality , 1998, International archives of occupational and environmental health.

[23]  S. Krähenbühl,et al.  Analysis and pharmacokinetics of glycyrrhizic acid and glycyrrhetinic acid in humans and experimental animals , 1994, Steroids.

[24]  T. Kimura,et al.  Mechanism of gastrointestinal absorption of glycyrrhizin in rats. , 1994, Biological & pharmaceutical bulletin.

[25]  H J Clewell,et al.  Incorporation of pharmacokinetics in noncancer risk assessment: example with chloropentafluorobenzene. , 1994, Risk analysis : an official publication of the Society for Risk Analysis.

[26]  W. Hop,et al.  Intravenous glycyrrhizin for the treatment of chronic hepatitis C: A double‐blind, randomized, placebo‐controlled phase I/II trial , 1999, Journal of gastroenterology and hepatology.

[27]  S. Krähenbühl,et al.  Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans. , 1994, The Journal of clinical endocrinology and metabolism.

[28]  D. Morgan,et al.  Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease , 1995, Clinical pharmacokinetics.

[29]  T. Kimura,et al.  Pharmacokinetics of glycyrrhizin in rats with D-galactosamine-induced hepatic disease. , 1996, Biological & pharmaceutical bulletin.

[30]  A. Suzuki,et al.  Determination of 18β-glycyrrhetic acid in human plasma by high-performance liquid chromatography , 1994 .

[31]  K. Kobashi,et al.  Metabolism of glycyrrhizin by human intestinal flora. , 1983, Planta medica.

[32]  R. K. Meyer,et al.  Effect of androgen and estrogen on succinic dehydrogenase and cytochrome oxidase of rat prostate and seminal vesicle. , 1949, Endocrinology.

[33]  K. Kobashi,et al.  Hydrolysis of glycyrrhizin to 18 beta-glycyrrhetyl monoglucuronide by lysosomal beta-D-glucuronidase of animal livers. , 1991, Biochemical pharmacology.

[34]  K. Kobashi,et al.  Glycyrrhizin beta-D-glucuronidase of Eubacterium sp. from human intestinal flora. , 1987, Chemical & pharmaceutical bulletin.

[35]  J. Virjee,et al.  Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. , 1990, BMJ.

[36]  J. Alexander,et al.  Glycyrrhizic acid in liquorice--evaluation of health hazard. , 1993, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[37]  P B Laub,et al.  NCOMP--a windows-based computer program for noncompartmental analysis of pharmacokinetic data. , 1996, Journal of pharmaceutical sciences.

[38]  E. Hogendoorn,et al.  Improvement of selectivity and sensitivity by column switching in the determination of glycyrrhizin and glycyrrhetic acid in human plasma by high-performance liquid chromatography. , 1988, Journal of chromatography.

[39]  S. Ishida,et al.  Prediction of glycyrrhizin disposition in rat and man by a physiologically based pharmacokinetic model. , 1990, Chemical & pharmaceutical bulletin.

[40]  L. Benet,et al.  Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? , 1992, Drug metabolism reviews.

[41]  Brouwer,et al.  glycyrrhizin as a potential treatment for chronic hepatitis C , 1998, Alimentary pharmacology & therapeutics.

[42]  G. Fenwick,et al.  The determination of glycyrrhizin in selected UK liquorice products. , 1990, Food additives and contaminants.

[43]  H. Kotaki,et al.  Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method. , 1992, Journal of pharmaceutical sciences.

[44]  Y. Akada,et al.  Rapid estimation of glycyrrhizin and glycyrrhetinic acid in plasma by high-speed liquid chromatography. , 1979, Chemical & pharmaceutical bulletin.

[45]  G. Fenwick,et al.  Liquorice, Glycyrrhiza glabra L.—Composition, uses and analysis , 1990 .

[46]  C. Beglinger,et al.  Influence of age, gender, hormonal status and smoking habits on colonic transit time , 1995, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[47]  H J Clewell,et al.  Applying simulation modeling to problems in toxicology and risk assessment--a short perspective. , 1995, Toxicology and applied pharmacology.

[48]  M. Aburada,et al.  Determination of glycyrrhetic acid in human serum by high-performance liquid chromatography with ultraviolet detection. , 1990, Journal of Chromatography A.

[49]  T. Tsai,et al.  Pharmacokinetics of glycyrrhizin after intravenous administration to rats. , 1992, Journal of pharmaceutical sciences.

[50]  S. Ishida,et al.  Pharmacokinetics of glycyrrhetic acid, a major metabolite of glycyrrhizin, in rats. , 1989, Chemical & pharmaceutical bulletin.

[51]  S F Phillips,et al.  Variability of gastrointestinal transit in healthy women and men. , 1996, Gut.

[52]  S. Ishida,et al.  Binding of glycyrrhizin to human serum and human serum albumin. , 1989, Chemical & pharmaceutical bulletin.

[53]  S. Ishida,et al.  Dose-dependent pharmacokinetics of glycyrrhizin in rats. , 1992, Chemical & pharmaceutical bulletin.

[54]  D. Morris,et al.  Medicinal uses of licorice through the millennia: The good and plenty of it , 1991, Molecular and Cellular Endocrinology.

[55]  K. Hierholzer,et al.  Endogenous inhibitors of 11β-OHSD: Existence and possible significance , 1994, Steroids.

[56]  Y. Motohashi,et al.  Liver transferase activity in healthy Japanese employees aged 18-39 years. , 1998, Industrial health.

[57]  J Meulenbelt,et al.  A population physiologically based pharmacokinetic/pharmacodynamic model for the inhibition of 11-beta-hydroxysteroid dehydrogenase activity by glycyrrhetic acid. , 2001, Toxicology and applied pharmacology.

[58]  J. Lin,et al.  Dose‐dependent pharmacokinetics: Experimental observations and theoretical considerations , 1994, Biopharmaceutics & drug disposition.

[59]  J Meulenbelt,et al.  Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling. , 2000, Toxicology and applied pharmacology.

[60]  B. Walker,et al.  Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. , 1994, Endocrinology and metabolism clinics of North America.

[61]  T. Akao.  Hydrolysis of glycyrrhetyl mono-glucuronide to glycyrrhetic acid by glycyrrhetyl mono-glucuronide beta-D-glucuronidase of Eubacterium sp. GLH. , 1997, Biological & pharmaceutical bulletin.

[62]  P. Hrelia,et al.  Interaction of licorice on glycyrrhizin pharmacokinetics. , 1994, Environmental health perspectives.

[63]  J. DeJongh,et al.  Simulation of toluene kinetics in the rat by a physiologically based pharmacokinetic model with application of biotransformation parameters derived independently in vitro and in vivo. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[64]  S. Ishida,et al.  Disposition of glycyrrhizin in the perfused liver of rats. , 1994, Biological and Pharmaceutical Bulletin.

[65]  L. D. O'Donnell,et al.  An office guide to whole-gut transit time. Patients' recollection of their stool form. , 1994, Journal of clinical gastroenterology.

[66]  K. Kobashi,et al.  Intestinal bacterial hydrolysis is indispensable to absorption of 18β‐glycyrrhetic acid after oral administration of glycyrrhizin in rats , 1994, The Journal of pharmacy and pharmacology.

[67]  E M Faed,et al.  Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs. , 1984, Drug metabolism reviews.

[68]  K. Kobashi,et al.  Bioavailability Study of Glycyrrhetic Acid after Oral Administration of Glycyrrhizin in Rats; Relevance to the Intestinal Bacterial Hydrolysis , 1996, The Journal of pharmacy and pharmacology.

[69]  T. Nakada,et al.  Synthesis and separation of 18 beta-glycyrrhetyl monoglucuronide from serum of a patient with glycyrrhizin-induced pseudo-aldosteronism. , 1986, Chemical & pharmaceutical bulletin.

[70]  Masao Hattori,et al.  Hydrolysis of glycyrrhizin to 18β-glycyrrhetyl monoglucuronide by lysosomal β-D-glucuronidase of animal livers , 1991 .

[71]  H. Kotaki,et al.  The relationship between pharmacokinetic behaviour of glycyrrhizin and hepatic function in patients with acute hepatitis and liver cirrhosis , 1995, Biopharmaceutics & drug disposition.

[72]  A. Olukoga,et al.  Historical perspectives on health The history of liquorice: the plant, its extract, cultivation, commercialisation and etymology , 1998, The journal of the Royal Society for the Promotion of Health.

[73]  S. Krähenbühl,et al.  Determination of 18β-glycyrrhetinic acid in biological fluids from humans and rats by solid-phase extraction and high-performance liquid chromatography , 1993 .