A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling

Purpose, To analyze the role of the kinetics of glycyrrhizic acid (GD) in i ts toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD. which is absorbed as glycyrrhetic acid (GA), w ere described by a human PBPK model, which is based on a rat model. After r at to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual va riability in kinetics was quantified by deriving an optimal set of paramete rs for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA m etabolites. The optimized model explained most of the interindividual varia nce, observed in the clinical study. and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated i n the human PBPK model. Model simulations demonstrate that especially in su bjects with prolonged gastrointestinal residence limes, GA may accumulate a fter repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.