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A Human Physiologically-Based Model for Glycyrrhzic Acid, A Compound Subject to Presystemic Metabolism and Enterohepatic Cycling

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Abstract

Purpose. 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.

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Authors and Affiliations

  1. LAP&P Consultants BV, Kenniscentrum Archimedesweg 31, 2333 CM, The Netherlands

    Bart Ploeger

  2. Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands

    Bart Ploeger

  3. National Poisons Control Centre, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands

    Tjeert Mensinga & Jan Meulenbelt

  4. Department of Intensive Care and Clinical Toxicology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands

    Tjeert Mensinga & Jan Meulenbelt

  5. Laboratory for Exposure Assessment and Environmental Epidemiology, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands

    Adriënne Sips

  6. Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands

    Joost DeJongh

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  1. Bart Ploeger
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  2. Tjeert Mensinga
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  5. Joost DeJongh
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Ploeger, B., Mensinga, T., Sips, A. et al. A Human Physiologically-Based Model for Glycyrrhzic Acid, A Compound Subject to Presystemic Metabolism and Enterohepatic Cycling. Pharm Res 17, 1516–1525 (2000). https://doi.org/10.1023/A:1007661209921

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