Prediction of Glycyrrhizin disposition in rat and man with liver failure by a physiologically based pharmacokinetic model.

Two physiologically based pharmacokinetic models A and B incorporating enterohepatic recycling, which succeeded previously in predicting the disposition of glycyrrhizin (GLZ) in normal rats and subjects, were applied to predict GLZ disposition in plasma and tissues of chronically CCl4-intoxicated rats, and serum of humans with hepatitis after i.v. dosing. The prediction by model A with the direct excretion of GLZ from liver into gut lumen gave fairly good agreement with the observed time courses of GLZ concentrations in blood and tissues in the intoxicated rats. The human serum disposition was predicted by model B, to which was added a gallbladder for the excretion from liver into gut lumen to model A by assuming continuous delaying transfer from the gallbladder. An attempt to predict the serum dispositions in five human subjects by considering individual differences in serum free fraction, biliary excretion ratio, and intestinal absorption clearance was successful in model B. Thus, scale-up of the disposition kinetics of GLZ from rat to man with liver failure was successful.