A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling.
OBJECTIVE
To analyze the role of the kinetics of glycyrrhizic acid (GD) in its 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), were described by a human PBPK model, which is based on a rat model. After rat 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 variability in kinetics was quantified by deriving an optimal set of parameters 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 metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature.


CONCLUSIONS
Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.
Ploeger
B
B
LAP&P Consultants BV, Leiden, The Netherlands. b.ploeger@lapp.nl
Mensinga
T
T
Sips
A
A
Meulenbelt
J
J
DeJongh
J
J
D000328:Adult; D000465:Algorithms; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D003198:Computer Simulation; D018592:Cross-Over Studies; D004764:Enterohepatic Circulation / Q000502:physiology*; D005260:Female; D019695:Glycyrrhizic Acid / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D015203:Reproducibility of Results
D000890:Anti-Infective Agents; D019695:Glycyrrhizic Acid