KINETICS AND DYNAMICS OF ORALLY-ADMINISTERED 18-BETA-GLYCYRRHETINIC ACID IN HUMANS

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of gly cyrrhizic acid (glycyrrhizin), an important constituent of licorice an d licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid d ehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, o r 1500 mg) were administered to healthy volunteers in order to study i ts kinetics and dynamics. In agreement with the lipophilic nature of G RA, the kinetics are characterized by extensive distribution into tiss ues, with a biphasic decay of the plasma concentration-time curve at d oses greater than 500 mg. The mean (+/-SEM) half-life of the second el imination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with i ncreasing GRA doses. Urinary elimination of GRA and GRA glucuronides o ver 24 h was less than 1% of the dose administered. The dynamics of GR A were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, an d the cortisol/cortisone ratio increased. Both peak plasma concentrati on and AUCs of GRA correlated with changes in the AUC values of cortis one. Based on the single dose kinetics, the kinetic/dynamic analysis o f the data revealed that after multiple doses of 1.5 g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 50 0 mg or less, such an inhibition might occur only transiently.