Pharmacokinetics Of Glycyrrhizin Research Articles

Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3.

Intravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated into the management of liver diseases in China. This investigation was designed to elucidate the molecular mechanism underlying hepatobiliary excretion of glycyrrhizin and to investigate its potential for drug-drug interactions on organic anion-transporting polypeptide (OATP)1B. Human transporters mediating hepatobiliary excretion of glycyrrhizin were characterized at the cellular and vesicular levels and compared with rat hepatic transporters. The role of Oatp1b2 in glycyrrhizin's elimination and pharmacokinetics was evaluated in rats using the inhibitor rifampin. A physiologically based pharmacokinetic (PBPK) model for glycyrrhizin, incorporating transporter-mediated hepatobiliary excretion, was established and applied to predict potential drug-drug interactions related to glycyrrhizin in humans. Hepatobiliary excretion of glycyrrhizin involved human OATP1B1/1B3 (Oatp1b2 in rats)-mediated hepatic uptake from blood and human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (ABCP)/bile salt export pump (BSEP)/multidrug resistance protein 1 (Mrp2/Abcp/Bsep in rats)-mediated hepatic efflux into bile. In rats, rifampin impaired hepatic uptake of glycyrrhizin significantly increasing its systemic exposure. Glomerular-filtration-based renal excretion of glycyrrhizin was slow due to extensive protein binding in plasma. Quantitative analysis using the PBPK model demonstrated that OATP1B1/1B3 have critical roles in the pharmacokinetics of glycyrrhizin, which is highly likely to be a victim of drug-drug interactions when co-administered with potent dual inhibitors of these transporters. Transporter-mediated hepatobiliary excretion governs glycyrrhizin's elimination and pharmacokinetics. Understanding glycyrrhizin's potential drug-drug interactions on OATP1B1/1B3 should enhance the therapeutic outcome of glycyrrhizin-containing drug combinations on liver diseases.

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 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.

Effects of glucose, fructose and 5-hydroxymethyl-2-furaldehyde on the presystemic metabolism and absorption of glycyrrhizin in rabbits

Our previous study reported that co-administration of honey significantly increased the serum levels of glycyrrhetic acid (GA) after oral administration of glycyrrhizin (GZ) in rabbits. The components of honey are sucrose, glucose, fructose and 5-hydroxymethyl-furaldehyde (HMF). To clarify the causative component(s) in honey that altered the metabolic pharmacokinetics of GZ, rabbits were given GZ (150 mg kg(-1)) with and without glucose (5 g/rabbit), fructose (5 g/rabbit) and HMF (1 mg kg(-1)), respectively, in crossover designs. An HPLC method was used to determine concentrations of GZ and GA in serum as well as GA and 3-dehydroglycyrrhetic acid (3-dehydroGA) in faeces suspension. A noncompartment model was used to calculate the pharmacokinetic parameters and analysis of variance was used for statistical comparison. Our results indicated that the area under curve (AUC) of GA was significantly increased by 29% when HMF was coadministered, whereas the pharmacokinetics of GZ and GA were not significantly altered by coadministration of glucose or fructose. An in-vitro study, using faeces to incubate GZ and GA individually, indicated that HMF significantly inhibited the oxidation of GA to 3-dehydroGA and this may explain the enhanced GA absorption in-vivo. It was concluded that HMF is the causative component in honey that affects the presystemic metabolism and pharmacokinetics of GZ in-vivo.

Pharmacokinetics of glycyrrhizin in normal and albumin‐deficient rats

The pharmacokinetics of glycyrrhizin (GZ) was compared in albumin-deficient rats (NAR) and normal rats (SDR) after intravenous administration. The study sought to clarify the relationship between GZ concentration and its elimination rate in serum, liver and bile when the serum protein binding of GZ decreased. Serum protein binding in SDR and NAR, respectively, was 99.7% and 68.2% for a GZ concentration of 2.5 microg/ml. At steady-state conditions after i.v. infusion of GZ (0.5-2.0 mg/h), the relationship between the GZ concentration in serum and liver was linear in the SDR but nonlinear in the NAR. For both NAR and SDR, the GZ liver level and the elimination rate was nonlinear, indicating that the elimination of GZ from liver into bile was the rate-limiting step regardless of serum protein binding, and that the liver GZ level was extremely high when serum protein binding was decreased. It is concluded that a typical dose of GZ in chronic hepatitis patients whose serum albumin level is low will not cause a decrease of therapeutic effect compared with patients with a normal serum albumin level.

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 11β-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.

Pharmacokinetic Difference between Licorice and Honey-processed Licoricein Rabbits

Objectives. Licorice and honey-processed licorice are widely used in clinical Chinese medicine for a variety of conditions and ailments. In this study, we investigated the difference in pharmacokinetics between unprocessed licorice and honey-processed licorice. Methods. Six rabbits were given decoctions of unprocessed licorice and honey-processed licorice in a crossover design. The concentrations of glycyrrhizin and glycyrrhetic acid in serum as well as glycyrrhetic acid in feces suspension were determined by HPLC methods. The pharmacokinetic parameters were calculated by a noncompartment model and statistical comparison was made by paired Student's t test. Results. No significant difference in pharmacokinetics of glycyrrhizin was found between the two treatments; however, licorice processed with honey increased the AUC of glycyrrhetic acid by 48%. The hydrolysis of glycyrrhizin to glycyrrhetic acid in feces suspension was greatly enhanced by the addition of honey. Conclusions. Honey processing of licorice affected the presystemic metabolism of glycyrrhizin and resulted in the elevation of blood levels of glycyrrhetic acid, which indicates that honey might increase the efficacy and toxicity of licorice. ( Mid Taiwan J Med 2004;9:73-9 )

Influence of honey on the gastrointestinal metabolism and disposition of glycyrrhizin and glycyrrhetic acid in rabbits.

To investigate the effects of honey on the pharmacokinetics of glycyrrhizin and glycyrrhetic acid, administration of glycyrrhizin or glycyrrhetic acid with and without honey was carried out in rabbits in a randomized crossover design. An in vitro study using rabbit fecal flora was employed to elucidate the mechanism of the interaction. HPLC methods were used for the determination of glycyrrhizin, glycyrrhetic acid and 3-dehydroglycyrrhetic acid concentrations in serum and feces. Paired and unpaired Student's t-tests were used for statistical comparisons for in vivo and in vitro studies, respectively. Our study indicated that the area under the curve (AUC0-t) of glycyrrhetic acid was significantly enhanced by 53% when honey was concomitantly given with glycyrrhizin, whereas that of glycyrrhizin was not significantly altered. Nevertheless, lack of effect was observed when honey was concurrently given with glycyrrhetic acid. Fecal study indicated that both the hydrolysis of glycyrrhizin to glycyrrhetic acid and subsequent oxidation of glycyrrhetic acid to 3-dehydroglycyrrhetic acid were significantly affected in the presence of honey to result in more glycyrrhetic acid available for absorption. It could be concluded that honey significantly affected the gastrointestinal metabolism of glycyrrhizin and resulted in the increased glycyrrhetic acid exposure. Therefore, honey might enhance the efficacy and adverse effects of glycyrrhizin.

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon‐tetrachloride‐intoxicated rats

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon‐tetrachloride‐intoxicated rats

Pharmacokinetics of Glycyrrhizin in Rats with D-Galactosamine-Induced Hepatic Disease.

The pharmacokinetic behavior of glycyrrhizin (GZ) was examined in D-galactosamine-intoxicated (GAL) rats. When GZ was administered intravenously, the apparent volume of distribution (Vdss) and the total body clearance (CLtotal) were more significantly decreased in GAL rats than those in normal rats. When GZ was administered orally, the area under the plasma concentration-time curve (AUC), the mean residence time (MRT) and the time to reach the maximum plasma concentration (Tmax) for GZ were higher, but the maximum plasma concentration (Cpmax) in GAL rats was lower than that in normal rats. The bioavailability of GZ, however, was not significantly changed. On the other hand, the AUC for glycyrrhetic acid (GA), a main metabolite of GZ, after oral administration of GZ was higher in GAL rats than in normal rats, although there was no significant difference in MRT or Tmax, Cpmax or the bioavailability for GA between GAL and normal rats. The reasons for these differences in GAL rats would be changes in the absorption rate (reduced gastric emptying rate) and reduction of the hepatic elimination rates (biliary excretion of GZ and hepatic metabolism of GA).

Interaction of licorice on glycyrrhizin pharmacokinetics.

The effects of components of aqueous licorice root extract (LE) on the pharmacokinetics of glycyrrhizin (G) and glycyrrhetic acid (GA) were investigated in rats and humans. The aim of this work was to define the role of pharmacokinetics in G toxicity. In the procedure, G and GA were detected in biological fluids by means of recently improved HPLC methods. Significantly lower G and GA plasma levels were found in rats and humans treated with LE compared to the levels obtained with those in which G alone was administered. The pharmacokinetic curves showed significant differences in the areas under the plasma-time curve (AUC), Cmax, and Tmax parameters. The data obtained from urine samples are in agreement with the above results and confirm a reduced bioavailability of G present in LE compared to pure G. This should be attributed to the interaction during intestinal absorption between the G constituent and the several components in LE. The modified bioavailability could explain the various clinical adverse effects resulting from the chronic oral administration of G alone as opposed to LE.

Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis.

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half-life (t1/2) and the total body clearance (CLtot) were 6.0 h (range 4.3-10.7 h) and 7.9 ml h-1 kg-1 (4.5-12.7 ml h-1 kg-1), respectively. The variation of the CLtot for G was closely related to that of aspartate aminotransferase (r = -0.739, p < 0.05) and alanine aminotransferase (r = -0.783, p < 0.05) activities in the plasma.

Pharmacokinetics of Glycyrrhizin after Intravenous Administration to Rats

AbstractA simple high‐performance liquid chromatographic method was developed to study the pharmacokinetics of glycyrrhizin in the rat after bolus intravenous administration at a dose of 20, 50, or 100 mg/kg. The decline in the concentration of glycyrrhizin in plasma was generally biexponential at each dose, but the terminal disposition became much slower as the dose was increased. A greater‐than‐proportional increase in the glycyrrhizin concentration in plasma was observed with an increase in the dose, a result suggesting a dose‐dependent glycyrrhizin disposition. The disposition of drug in plasma at each dose fitted well to a two‐compartment pharmacokinetic model. The apparent total body clearance decreased significantly with increases in the dose. On the other hand, the apparent distribution volume after intravenous administration was unaffected by the dose. The results indicate that the pharmacokinetics of glycyrrhizin is nonlinear.

Gas Chromatography-Selected Ion MonitoringによるFM-100投与後の血中グリチルリチン及びグリチルレチン酸の定量

Glycyrrhizin and glycyrrhetinic acid in the human plasma after administration of FM-100 (the powder obtained from acidic fraction of methanolic extract of Glycyrrhiza) were determined by capillary gas chromatography-selected ion monitoring by using [2H5]glycyrrhetinic acid methyl ester as an internal standard. Plasma was subjected to direct hydrolysis, and the resulting mixture was adsorbed on a polyamide column. Glycyrrhetinic acid was eluted with methanol, and the eluant was further purified by a Sep-Pak Silica cartridge and a silicagel column after the addition of the internal standard. Glycyrrhetinic acid, a metabolite of glycyrrhizin, was directly extracted with AcOEt from the plasma with high recovery. Glycyrrhetinic acid extracted was converted to its methyl ester-O-trimethylsilyl ether derivative by treating with diazomethane and then with N, O-bis-(trimethylsilyl) trifluoroacetamide. Monitoring of the molecular ion indicated that the quantitation limit for glycyrrhizin was 1 ng/ml plasma. After oral administration of 400 mg of FM-100, plasma levels of glycyrrhizin and glycyrrhetinic acid were shown with a maximum at 8-14 h post dose period. For the study of bioavailability of glycyrrhizin, each subject was indispensable to fast in order to avoid the effect of natural glycyrrhizin from many food additives for more than 10 h before and after administration of FM-100, respectively. This method was useful for the study on pharmacokinetics of glycyrrhizin and glycyrrhetinic acid, because of having sufficient sensitivity and specificity for objective compounds.