Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review.

Licorice (Glycyrrhiza glabra) has been considered as an herbal drug since ancient time. Nowadays, it is a well-known spice that possesses worth pharmacological effects. However, some relevant articles have revealed negative impacts of licorice in health. By considering the great wishes in using herbal medicine, it is important to show adverse effects of herbal medicine in health. At present, there are misunderstandings toward the safety of herbal medicines. Herein, we gathered scientific research projects on the toxicity effects of licorice and glycyrrhizin to highlight their safety. In this regards, we categorized our findings about the toxicity effects of licorice and glycyrrhizin in acute, sub-acute, sub-chronic, and chronic states. Besides, we discussed on the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of licorice and glycyrrhizin as well as their developmental toxicity. This review disclosed that G. glabra and glycyrrhizin salts are moderately toxic. They need to be used with caution during pregnancy. G. glabra and glycyrrhizin possess selective cytotoxic effects on cancerous cells. The most important side effects of licorice and glycyrrhizin are hypertension and hypokalemic-induced secondary disorders. Licorice side effects are increased by hypokalemia, prolonged gastrointestinal transient time, decreased type 2 11-beta-hydroxysteroid dehydrogenase activities, hypertension, anorexia nervosa, old age, and female sex. Copyright © 2017 John Wiley & Sons, Ltd.

Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1.

High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. Although glycyrrhizin was known as inhibitor of HMGB1, it is not yet clear underlying mechanism(s). We found that glycyrrhizin activates translocation of Nrf2 from cytosol to nucleus and induces heme oxygenase (HO)-1 expression in RAW 264.7 cells. In addition, deletion of Nrf2 by siRNA significantly reduced mRNA expression of NQO1 and HO-1 suggesting that glycyrrhizin targets Nrf2 gene. The expression of iNOS protein and release of HMGB1 in LPS activated cells were significantly reduced by glycyrrhizin and cells transfected with mouse HO-1 expression vector. The p38MAPK inhibitor (SB203580) but not JNK inhibitor (SP600125) or ERK inhibitor (PD98059) significantly inhibited HO-1 induction by glycyrrhizin, which was confirmed by showing that siP38 transfected cells significantly reduced HO-1 induction. Pretreatment with SB203580 significantly reversed the expression of iNOS and release of NO and HMGB1 in LPS-activated cells. Most importantly, administration of glycyrrhizin (200mg/kg, i.p) significantly reduced hepatic injury and serum HMGB1 in a ZnPPIX-sensitive manner. Thus, it is concluded that glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1.

Comparison of the exposure of glycyrrhizin and its metabolites and the pseudoaldosteronism after intravenous administration of alpha- and beta-glycyrrhizin in rat.

Glycyrrhizin, the major bioactive component in licorice root extract, exists as 2 isomers, α and ß-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 ß-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 ß-isomer and the AUC0-24 h values of glycyrrhizin and the metabolites were all significantly higher in ß 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 ß-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 ß group. The urinary cortisol:cortisone ratio was higher in rats given ß-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 ß- glycyrrhizin probably due to a lower systemic exposure to the 2 metabolites.

Glycyrrhizin-modified O-carboxymethyl chitosan nanoparticles as drug vehicles targeting hepatocellular carcinoma.

Here we describe the O-carboxymethyl chitosan nanoparticles (CMCNP) modified by glycyrrhizin (GL) with various substitution degrees as hepatocellular carcinoma (HCC)-targeted delivery vehicles, which could efficiently deliver paclitaxel (PTX) into HCC. The resultant CMCNP-GL exhibited spherical in shape and high stability in plasma with fixed negative charged (~-30 mV) and a size range of 100-205 nm. PTX was loaded into CMCNP-GL with a maximal encapsulation efficiency of 83.7% and performed a biphasic release. CMCNP-GL promoted liver cancer SMMC-7721 cell internalization by approximate 10.0-fold as compared to unmodified CMCNP. Within 72 h, the IC(50) of PTX/CMCNP-GL, PTX/CMCNP, and PTX injection was 2.7-3.2, 8.1, and 13.5 µg/mL, respectively. Biodistribution experiments revealed that PTX/CMCNP-GL exerted significantly superior targeting to tumor than PTX/CMCNP. The in vivo tumor inhibition ratio of PTX/CMCNP-GL was 87.5%, showing remarkably higher than that of PTX/CMCNP (64.0%) and PTX injection (34.5%). CMCNP-GL with different substitution degrees possessed similar targeting property and therapeutic efficacy. Furthermore, toxicity studies suggested that blank CMCNP-GL had no systemic or hepatic toxicity.

Piper sarmentosum prevents glucocorticoid-induced osteoporotic bone resorption by increasing 11ß-hydroxysteroid dehydrogenase type 1 activity.

AIMS: Osteoporosis is a proven complication of long-term glucocorticoid therapy. Concern on glucocorticoid induced osteoporosis has increased dramatically in recent years with the widespread use of synthetic glucocorticoids. Glucocorticoid action in bone depends upon the activity of 11ßhydroxysteroid dehydrogenase type 1 enzyme (11ßHSD1). This enzyme plays an important role in regulating corticosteroids by locally interconverting cortisone into active cortisol. This has been demonstrated in primary cultures of human, mouse or rat osteoblasts. Therefore, inhibition of this enzyme may reduce bone resorption markers. Piper sarmentosum (Ps) is a potent inhibitor of 11ßHSD1 in liver and adipose tissue. In this study we determined the effect of Ps on 11ßHSD1 activity in bones of glucocorticoid-induced osteoporotic rats. MATERIALS AND METHODS: Three-month old male Sprague-Dawley rats were adrenalectomised to remove the main source of circulating glucocorticoids. The animals were administered with dexamethasone 120 µg/kg body weight/day. Treatment with Ps 125 mg/kg body weight and glycirrhizic acid (GCA) 120 mg/kg body weight were given simultaneously. RESULTS: The results showed that Ps extract reduced plasma corticosterone concentration (1.05+0.02 µg/ml) and induced 11ßHSD1 dehydrogenase activity in bone (87.69+1.41%). Consequently, it also reduced the bone resorption marker, pyridinoline, in dexamethasone-treated adrenalectomised rats (2.07+0.62/L). Despite that, our data showed an inverse relationship between the plasma corticosterone level and the dehydrogenase activity of 11ßHSD1 in the bone. CONCLUSIONS: This suggests that 11ßHSD1 acts as the local regulator of glucocorticoid and its activity in bone was not correlated to systemic corticosterone level.

Glycyrrhizin as antiviral agent against Hepatitis C Virus.

BACKGROUND: Hepatitis C virus is a major cause of chronic liver diseases which can lead to permanent liver damage, hepatocellular carcinoma and death. The presently available treatment with interferon plus ribavirin, has limited benefits due to adverse side effects such as anemia, depression, fatigue, and "flu-like" symptoms. Herbal plants have been used for centuries against different diseases including viral diseases and have become a major source of new compounds to treat bacterial and viral diseases. MATERIAL: The present study was design to study the antiviral effect of Glycyrrhizin (GL) against HCV. For this purpose, HCV infected liver cells were treated with GL at non toxic doses and HCV titer was measured by Quantitative real time RT-PCR. RESULTS AND DISCUSSION: Our results demonstrated that GL inhibit HCV titer in a dose dependent manner and resulted in 50% reduction of HCV at a concentration of 14 ± 2 µg. Comparative studies were made with interferon alpha to investigate synergistic effects, if any, between antiviral compound and interferon alpha 2a. Our data showed that GL exhibited synergistic effect when combined with interferon. Moreover, these results were verified by transiently transfecting the liver cells with HCV 3a core plasmid. The results proved that GL dose dependently inhibit the expression of HCV 3a core gene both at mRNA and protein levels while the GAPDH remained constant. CONCLUSION: Our results suggest that GL inhibit HCV full length viral particles and HCV core gene expression or function in a dose dependent manner and had synergistic effect with interferon. In future, GL along with interferon will be better option to treat HCV infection.

Effect of licorice compounds licochalcone A, glabridin and glycyrrhizic acid on growth and virulence properties of Candida albicans.

Candida albicans is the predominant causal agent of candidiasis. Its ability to form hyphae and biofilm has been suggested to be key virulence factors. In this study, we investigated the effect of major licorice compounds licochalcone A, glabridin and glycyrrhizic acid on growth, biofilm formation and yeast-hyphal transition of C. albicans. The synergistic effect of licorice compounds with the antifungal drug nystatin was also evaluated. Minimal inhibitory concentrations (MICs) for C. albicans were determined using a microplate dilution assay. The synergistic effect with nystatin was determined similarly. The effect of licorice compounds on biofilm formation was evaluated using a microplate assay and crystal violet staining. The effect of licorice compounds on yeast-hyphal transition was determined by microscopic observation. The toxicity of licorice compounds towards oral epithelial cells was evaluated with an MTT assay. Glabridin and licochalcone A showed antifungal activity on C. albicans while glycyrrhizic acid had no effect. Complete growth inhibition occurred with sub-inhibitory concentrations of nystatin with either glabridin or licochalcone A. Biofilm formation was inhibited by 35-60% in the presence of licochalcone A (0.2 µg ml(-1)). A strong inhibitory effect (>80%) on hyphal formation was observed with licochalcone A or glabridin (100 µg ml(-1)). Glabridin and licochalcone A at high concentrations showed toxicity towards oral epithelial cells. In summary, glabridin and licochalcone A are potent antifungal agents and may act in synergy with nystatin to inhibit growth of C. albicans. Licochalcone A has a significant effect on biofilm formation, while both licochalcone A and glabridin prevented yeast-hyphal transition in C. albicans. These results suggest a therapeutic potential of licochalcone A and glabridin for C. albicans oral infections.

Genotoxicity assessment of Pyungwi-san (PWS), a traditional herbal prescription.

ETHNOPHARMACOLOGICAL RELEVANCE: Pyungwi-san (PWS, Heii-san in Japanese) is a mixture of six herbs and is traditionally used in Northeast Asia (especially Korea and Japan) for the treatment of gastrointestinal disorder, such as dyspepsia and inappetance induced by gastric dilatation and gastrointestinal catarrh. AIM OF THE STUDY: Although PWS is a widely used herbal prescription in Korea and Japan, little information is available in the literature on the safety and toxicity of PWS. As part of a safety evaluation of PWS, the present study evaluated the potential genotoxicity of PWS using a standard battery of test. MATERIALS AND METHODS: We prepared PWS using a water extraction method and simultaneously extracted three compounds from PWS using high performance liquid chromatography. The PWS extract that was obtained was assayed for genotoxicity using the standard three tests recommended by the Korea Food and Drug Administration. These tests included the bacterial reverse mutation test (Ames test), the chromosomal aberration test using China hamster lung cells, and the micronucleus test using ICR mice. RESULTS: The Ames test showed that the PWS extract did not induce an increase in the number of revertant colonies compared with vehicle control at any dose in all of tester strains. In the micronucleus test, no significant increase was observed in micronucleated polychromatic erythrocytes (MNPCEs) at any dose of PWS extract compared with vehicle control. Conversely, chromosomal aberration test showed that the PWS extract at a dosage of 4500 µg/mL induced an increase in the number of chromosomal aberrations in the 6 h group with metabolic activation compared with the vehicle control. CONCLUSION: PWS extract exhibits genotoxicity, based on the results of the chromosomal aberration test. Thus, further detailed experiments will be needed to identify the ingredient responsible for inducing this genotoxicity and to determine its mechanism.

Glycidipine, a promising hypotensive and cardioprotective agent.

Toxicological pharmacological study of the molecular complex of nifedipine and glycyrrhizic acid 1:10 (glycidipine) obtained using mechanochemical technique was carried out. High hypotensive and cardioprotective effects of the agent were demonstrated. Chronic administration (45 days) produced no toxic effects in vital organs and systems of Wistar rats and ISIAH rats.

[Improvement of the pharmacological activity of nifedipine by mechanochemical complexation with glycyrrhizic acid].

A new water-soluble form of the calcium blocker nifedipine (NF) with glycyrrhizic acid (GA) (with molecular ratio 1:4) has been obtained by mechanochemical synthesis. Its pharmacological advantages in comparison with nifedipine were determined. An effective dose of nifedipine in complex reduced to 10 times as compared to its therapeutic dose while high antihypertensive activity preservation and pleiotropic antiarhythmic activity enhancement. This new antihypertensive and antiarhythmic agent (complex of NF:GA = 1:4) is chemically stable and safe for parenteral administration.

[Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides].

New glycyrrhizic acid (GA) conjugates were synthesized with the use of tert-butyl esters of amino acids or benzyl esters of dipeptides; they contained two residues of L-amino acids (Met, Phe, Pro, and Ile or dipeptides Gly-Leu and Gly-Phe). Activation of GA carboxy groups was carried out with the help of N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide, or N-hydroxybenzotriazole with dicyclohexylcarbodiimide. A proline-containing GA derivative is a low-toxic substance; it raises the level of agglutinins by 3.7 times in the blood of mice and 3 times that of hemolysins compared with the control. Dipeptide GA derivatives possess an expressed anti-HIV-1 activity in cultures of MT-4 cells and are 90-70 times less cytotoxic than azidothymidine. The selectivity index of the compounds exceeds those of GA by 110 and 34 times, respectively.

[Cholesterol lowering properties of a complex compound simvastatin with glycyrrhizic acid (simvaglyzin) in experimental models].

A molecular complex of simvastatin (SV) and glycyrrhyzic acid (GA) (at the ratio of 1 : 4), has been synthesized. The complex named "simvaglyzin" (SVG) was stable in aqeous and aqua-alcohol solutions at GA concentrations exceeding 0.2 mM. In vitro SVG acted as uncompetitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (Ki = 94 nM). Appearance of this inhibitory activity is associated with the cytochrome P450-dependent conversion of SVG. The addition of 1 mM methyrapone into incubation medium fully prevented the inhibition of 3-HMG-CoA reductase. SV and SVG (used at 300 nM concentration) inhibited mevalonate synthesis rate by 39.15+/-8.27% and 38.85+/-3.04%, respectively. In vivo SVG showed dose-dependent cholesterol-lowering effect. In rats the cholesterol-lowering effect of SVG used at daily doses corresponding to 66 and 100 mg/kg of SV was equal to the effect of the daily dose 200 mg/kg of SV. The decreases of total cholesterol level in blood serum were 7%, 9% and 8%, respectively. Myotoxicity of those SVG doses estimated by creatine phosphokinase (CPK) activity in blood serum was lower than that of SV. In rats treated with SV the activity of CPK increased by 79% (p<0.01), while in SVG treated rats by 30% and 36% (p<0.05). Any increase of hepatotoxicity markers alanine aminotransferse or aspartate aminotransferase in blood serum was not observed. The data suggest pharmacological synergism attributed to the SV-GA complex formation and elevated safety of the resultant complex compared with the parent compound.

Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads.

Medicinal plants have been traditionally used for treating liver diseases since centuries. Several leads from plant sources have been found as potential hepatoprotective agents with diverse chemical structures. Although, a big list of hepatoprotective phytomolecules was reported in the scientific literature, only a few were potent against various types of liver damages. Of which, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have largely attracted the scientific community. This review focuses discussion on the chemistry, biological activity, mode of action, toxicity, and future prospects of these leads.

A possible involvement of 3-monoglucuronyl-glycyrrhetinic acid, a metabolite of glycyrrhizin (GL), in GL-induced pseudoaldosteronism.

Glycyrrhizin (GL), a major ingredient of Glycyrrhiza Radix (licorice), is widely used to treat various disorders or as a sweetener. It is also known that GL occasionally induces pseudoaldosteronism. It is conceivable that the active form of GL in pseudoaldosteronism induction is glycyrrhetinic acid (GA). Although it is reported that 3-monoglucuronyl-glycyrrhetinic acid (3MGA) is detectable specifically in the plasma of patients with GL-induced hypokalemia, pharmacokinetics and a hypokalemia induction mode of action for 3MGA have not been clarified. We investigated the toxicokinetics of GL, GA and 3MGA in a single or multiple oral administration of GL. The results suggested that higher blood concentrations of 3MGA were maintained by the multiple administration compared to the single dose, whereas the concentrations of GA and GL showed no difference. We injected 3MGA intravenously and found that it can decrease the plasma potassium level (PPL) in vivo. It is clinically recommended to avoid a combination treatment of GL and furosemide. While treatment with a low dosage of furosemide had no effect on PPL, the multiple administration of GL and furosemide markedly decreased PPL compared to the effect of administering GL alone. In the single dosage regime, there was no difference between PPL after the combination treatment and after administering GL alone. Collectively, these findings suggested that accumulation of 3MGA may be involved in the pathogenesis of pseudoaldosteronism induced by chronic GL treatment.

Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin.

Licorice (or 'liquorice') is a plant of ancient origin and steeped in history. Licorice extracts and its principle component, glycyrrhizin, have extensive use in foods, tobacco and in both traditional and herbal medicine. As a result, there is a high level of use of licorice and glycyrrhizin in the US with an estimated consumption of 0.027-3.6 mg glycyrrhizin/kg/day. Both products have been approved for use in foods by most national and supranational regulatory agencies. Biochemical studies indicate that glycyrrhizinates inhibit 11beta-hydroxysteroid dehydrogenase, the enzyme responsible for inactivating cortisol. As a result, the continuous, high level exposure to glycyrrhizin compounds can produce hypermineralocorticoid-like effects in both animals and humans. These effects are reversible upon withdrawal of licorice or glycyrrhizin. Other in vivo and clinical studies have reported beneficial effects of both licorice and glycyrrhizin consumption including anti-ulcer, anti-viral, and hepatoprotective responses. Various genotoxic studies have indicated that glycyrrhizin is neither teratogenic nor mutagenic, and may possess anti-genotoxic properties under certain conditions. The pharmacokinetics of glycyrrhizin have been described and show that its bioavailability is reduced when consumed as licorice; this has hampered attempts to establish clear dose-effect levels in animals and humans. Based on the in vivo and clinical evidence, we propose an acceptable daily intake of 0.015-0.229 mg glycyrrhizin/kg body weight/day.

[Antiarrhythmic activity of alaglyzin].

The activity of alaglyzin, a new drug based on a clathrate complex of allapinine (well-known antiarrhythmic) with glycyrrhizic acid (GA), was studied on the models of arrhythmia induced by itraperitoneal injections of calcium chloride (CaCl2) and adrenaline (epinephrine) in rats. Alaglyzin is less toxic than allapinine (LD50 70 and 6 mg/kg, respectively), and the effective dose of the parent compound in the complex form is also about 12 times lower than that in the reference drug. The experiments showed a dose dependent action of alaglyzin. Pretreatment of the experimental animals with alaglyzin in a dose of 0.25 mg/kg prevented from the arrhythmia development in both tests, while a dose of 0.125 mg/kg was effective only in the CaCl2, test.

Evaluation of certain food additives.

This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, with a view to recommending acceptable daily intakes (ADIs) and to prepare specifications for the identity and purity of food additives. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of food additives (including flavouring agents) and contaminants, assessments of intake, and the establishment and revision of specifications for food additives. A summary follows of the Committee's evaluations of toxicological and intake data on various specific food additives (benzoyl peroxide, alpha-cyclodextrin, hexose oxidase from Chondrus crispus expressed in Hansenula polymorpha, lutein from Tagetes erecta L., peroxyacid antimicrobial solutions containing 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), steviol glycosides, D-tagatose, xylanases from Bacillus subtilis expressed in B. subtilis, zeaxanthin), flavouring agents, and a natural constituent (glycyrrhizinic acid). Annexed to the report are tables summarizing the Committee's recommendations for ADIs of the food additives, recommendations on the flavouring agents and natural constituent considered, changes in the status of specifications, and further information requested or desired.

Toxicologic evaluation of licorice extract as a cigarette ingredient.

Licorice extract (block, powder or liquid) may be applied to cigarette tobacco at levels of about 1-4% to enhance and harmonize the flavor characteristics of smoke, improve moisture holding characteristics of tobacco, and act as a surface active agent for ingredient application. Neat material pyrolysis studies, and smoke chemistry and biological activity studies (bacterial mutagenicity, cytotoxicity, micronucleus, and sub-chronic inhalation) with mainstream smoke, or mainstream smoke preparations from cigarettes containing various target levels (1.5-12%) of the licorice extracts were performed to provide data for an assessment of the use of licorice extract as a cigarette tobacco ingredient. At simulated tobacco burning temperatures up to 900 degrees C all forms of neat licorice extract pyrolyzed extensively, yielding small amounts of benzene, toluene, phenol and acetaldehyde with no indication that licorice extracts would transfer intact to mainstream smoke. As a single ingredient added to cigarette tobacco, block licorice extract at a target level of 12.5% increased smoke constituents including selected PAH, arsenic, lead, phenol and formaldehyde (on a TPM basis), while licorice extract powder (target level of 8% tobacco) increased select PAH, phenol and formaldehyde (on a TPM basis). Lower target application levels (including typical application levels) of block, powder or liquid licorice extract did not significantly alter the smoke chemistry profile. Biological tests indicated no relevant difference in the genotoxic or cytotoxic potential of either mainstream smoke (or smoke preparations) from cigarettes with added licorice extracts compared to control cigarettes. In sub-chronic 90-day rat inhalation studies, the mainstream smoke from cigarettes with 12.5% added block and 8% added powder licorice extract contained higher formaldehyde concentrations compared to control cigarette smoke. Female rats in the 12.5% block licorice extract exposure group displayed an increased incidence and severity of epithelial hyperplasia in the nose (level 2), with no relevant respiratory tract changes in the 8% powder licorice extract exposed rats. At the lower licorice extract application levels (1.25-5%), there was no indication of increased formaldehyde concentration in the smoke atmosphere and no relevant changes in respiratory tract tissues. Mineralcorticoid-like effects which have been associated with excess licorice ingestion were not found in any of the smoke inhalation studies. The results of these studies with various forms of licorice extract applied to cigarette tobacco suggest that adding licorice extract to cigarette tobacco at levels of < or =5% does not discernibly alter the smoke chemistry or biological effects normally associated with mainstream cigarette smoke.

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-beta-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.