Midazolam effect of licorice (radix glycyrrhizae) water extract on the pharmacokinetics and the pharmacodynamics of midazolam in healthy ssubjects

Background : Licorice, a core traditional herbal medicine, is frequently coadministered with the conventional medications in Korea. Several reports suggested that the licorice treatment induced the cytochrome P450 (CYP) in rats, especially for CYP3A isoform. However, no report has been addressed to the effect of licorice on midazolam, CYP3A substrate, in human. This study was performed to evaluate the effect of licorice on the disposition and pharmacodynamic effects of midazolam in human. Methods : One gram of freeze dried water extract of licorice (extraction ratio ; 25%) or placebo were orally administered divided in two times to 10 healthy male subjects for 7 days as one blind randomized crossover manner with 2 weeks washout. On the day after completion of 7 days pretreatment, multiple blood samples were drawn and urine was collected for 24 hours after oral dose of 7.5 mg midazolam. Psychomotor performance tests including digit span test and digit symbol substitution test were conducted for 4 hours after midazolam administration on each phase of midazolam treatment and before pretreatment of placebo or licorice extract. The plasma concentration of midazolam and 1-hydroxymidazolam were determined with using HPLC and pharmacokinetic parameters were estimated by noncompartmental method. Results : After 1 week treatment of licorice extract, the plasma clearance of midazolam was significantly increased (1.15+0.50 vs 1.59+0.81 L/min, p<0.05) and the half-life was shortened ( 2.07+0.74 vs 1.34+0.60 hr, p<0.05) compared to those obtained after placebo treatment. Mean AUC of midazolam was decreased from 102.13+28.84 ng/ml·hr to 85.06+48.51 ng/ml·hr after licorice treatment, but not significantly different (p=0.11). There was no significant changes in AUC and urinary amount of 1-hydroxymidazolam by licorice pretreatment. The changes in the score of psychomotor performance tests (DST and DSST) measured after midazolam dosing were not significantly different between placebo and licorice pretreatment . Conclusions : Licorice water extract seems to affect the disposition of midazolam in human, but it is suggested that the CYP3A4 induction is not the major mechanism of the interaction. Further studies are remained to evaluate the mechanism of the pharmacokineitc interaction between midazolam and licorice water extract.