Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling

Glycyrrhizic acid is currently of clinical interest for treatment of chroni c hepatitis. It is also applied as a sweetener in food products and chewing tobacco. In some highly exposed subgroups of the population, serious side effects such as hypertension and electrolyte disturbances have been reporte d. In order to analyze the health risks of exposure to this compound, the k inetics of glycyrrhizic acid and its active metabolites were evaluated quan titatively, Glycyrrhizic acid and its metabolites are subject to complex ki netic processes, including enterohepatic cycling and presystemic metabolism . In humans, detailed information on these processes is often difficult to obtain. Therefore, a model was developed that describes the systemic and ga strointestinal tract kinetics of glycyrrhizic acid and its active metabolit e glycyrrhetic acid in rats. Due to the physiologically based structure of the model, data from earlier in vitro and in vivo studies on absorption, en terohepatic cycling, and presystemic metabolism could be incorporated direc tly. The model demonstrates that glycyrrhizic acid and metabolites are tran sported efficiently from plasma to the bile, possibly by the hepatic transf er protein 3-alpha-hydroxysteroid dehydrogenase. Bacterial hydrolysis of th e biliary excreted metabolites following reuptake of glycyrrhetic acid caus es the observed delay in the terminal plasma clearance of glycyrrhetic acid . These mechanistic findings, derived from analysis of experimental data th rough physiologically based pharmacokinetic modeling, can eventually be use d for a quantitative health risk assessment of human exposure to glycyrrhiz ic acid containing products. (C) 2000 Academic Press.