The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling

Glycyrrhizic acid is widely applied as a sweetener in food products and che wing tobacco. In addition, it is of clinical interest for possible treatmen t of chronic hepatitis C. In some highly exposed subjects, side effects suc h as hypertension and symptoms associated with electrolyte disturbances hav e been reported. To analyze the relationship between the pharmacokinetics o f glycyrrhizic acid in its toxicity, the kinetics of glycyrrhizic acid and its biologically active metabolite glycyrrhetic acid were evaluated. Glycyr rhizic 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 glucuronid e 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 a cid conjugates will be reabsorbed. This parameter. which can be estimated n oninvasively, may serve as a useful risk estimator for glycyrrhizic-acid-in duced adverse effects, because in subjects with prolonged gastrointestinal transit times. glycyrrhetic acid might accumulate after repeated intake.