A Population Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Inhibition of 11-β-Hydroxysteroid Dehydrogenase Activity by Glycyrrhetic Acid
Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. Habitual consumption of this compound may lead to hypertension and electrolyte disturbances due to inhibition of 11-β-hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg glycyr...
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Published in: | Toxicology and applied pharmacology Vol. 170; no. 1; pp. 46 - 55 |
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Main Authors: | , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
San Diego, CA
Elsevier Inc
01-01-2001
Elsevier |
Subjects: | |
Online Access: | Get full text |
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Summary: | Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. Habitual consumption of this compound may lead to hypertension and electrolyte disturbances due to inhibition of 11-β-hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg glycyrrhetic acid/day for 5 days on 11-β-hydroxysteroid dehydrogenase activity was studied by measuring the cortisol–cortisone ratio in 24-h urine. A twofold increase in this ratio was observed. It took 4 days for the elevated urinary cortisol–cortisone ratio to return to the baseline ratio after cessation of the treatment. The pharmacokinetics of glycyrrhetic acid were studied after the first and last dose. Using data from a previously performed single-dose study and present multiple-dose treatment, a physiologically based pharmacokinetic model for glycyrrhetic acid was developed. The variability of the pharmacokinetics of glycyrrhetic acid in the population studied could be explained for a considerable part by interindividual differences in gastrointestinal transit of glycyrrhetic acid metabolites. The relationship between glycyrrhetic acid exposure and changes in urinary cortisol–cortisone ratio was described by a pharmacodynamic model, using nonlinear mixed-effect modeling. Literature data on the inhibitory effect of glycyrrhetic acid on 11-β-hydroxysteroid dehydrogenase activity under various exposure scenarios could be adequately described by the model. Due to the relationship between the pharmacokinetics of glycyrrhetic acid and its inhibitory effect on 11-β-hydroxysteroid dehydrogenase activity, reflected by a change in the urinary cortisol–cortisone ratio, this ratio might serve as a noninvasive marker to identify individuals at risk for glycyrrhizic acid over-consumption. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0041-008X 1096-0333 |
DOI: | 10.1006/taap.2000.9078 |