A population physiologically based pharmacokinetic/pharmacodynamic model for the inhibition of 11-beta-hydroxysteroid dehydrogenase activity by glycyrrhetic acid

Glycyrrhizic acid is widely applied as a sweetener in food products and che wing tobacco. Habitual consumption of this compound may lead to hypertensio n and electrolyte disturbances due to inhibition of 11-beta -hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg gl ycyrrhetic acid/day for 5 days on 11-beta -hydroxysteroid dehydrogenase act ivity 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 eleva ted 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 perform ed single-dose study and present multiple-dose treatment, a physiologically based pharmacokinetic model for glycyrrhetic acid was developed. The varia bility of the pharmacokinetics of glycyrrhetic acid in the population studi ed could be explained for a considerable part by interindividual difference s in gastrointestinal transit of glycyrrhetic acid metabolites. The relatio nship between glycyrrhetic acid exposure and changes in urinary cortisol-co rtisone ratio was described by a pharmacodynamic model, using nonlinear mix ed-effect modeling. Literature data on the inhibitory effect of glycyrrheti c acid on 11-beta -hydroxysteroid dehydrogenase activity under various expo sure scenarios could be adequately described by the model. Due to the relat ionship between the pharmacokinetics of glycyrrhetic acid and its inhibitor y effect on 11-beta -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 o ver-consumption. (C) zool Academic Press.