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

Abstract

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.

Glycyrrhizic acid induces apoptosis in WEHI-3 mouse leukemia cells through the caspase- and mitochondria-dependent pathways

“…It was reported that glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid are the biologically active compounds in Licorice (10). GA, one of the triterpenoid saponin glycoside, was found to protect PC12 cells from 1-methyl-4-phenylpyridinium-induced cytotoxicity (11).…”

Preparation of 10-hydroxycamptothecin-loaded glycyrrhizic acid-conjugated bovine serum albumin nanoparticles for hepatocellular carcinoma-targeted drug delivery

“…8D. As GL is mainly taken up into the liver, 30 GL-conjugated NPs display a better rate of cell uptake than unconjugated NPs.…”

“…Glycyrrhizic acid (GL; Figure 1B) is hepatoprotective 28 and has been used to clinically treat patients with chronic active hepatitis. 29 Studies have shown that GL is mainly taken up into the liver 30 and modified liposomes have displayed good livertaxis. 31,32 The surface of GL has been modified based on N-caproyl chitosan and confirmed as a vehicle for hepatocyte targeting.…”

The absorption features of glycyrrhizic acid in composition of drug "phosphogliv"

“…Активным метаболитом ГК является глицирретовая кислота (ГА), которая по активности значительно превосходит ГК [2,3]. Образование ГА происходит только под действием микрофлоры кишечника [4], доказательством чему является отсутствие ГА в плазме крыс с убитой микрофлорой [5,6]. Несмотря на то, что ГА по биологической активности превосходит ГК, именно последняя входит в состав лекарственных композиций.…”