Effect of licorice (radix glycyrrhizae) on the pharmacokinetics (PK) and pharmacodynamics (PD) of midazolam in healthy subjects

Licorice, a core traditional herb medicine, is frequently coadministered with conventional medications in Korea. A few reports suggested that licorice induced the cytochrome P450 (CYP) in animals, especially for CYP3A isoform. To evaluate the effect of licorice on the PK and PD of midazolam, a known CYP3A4 substrate, 1g licorice (freeze dried water extract: extraction ratio-25%) or placebo were orally administered (bid) to 10 healthy male subjects for 1 days as double blind randomized crossover manner. After oral dose of 7.5mg midazolam at 8th day of pretreatment, multiple blood samples were drawn up to 24 hours and psychomotor performance tests (Digit span test and Digit symbol substitution test) were conducted for 4 hours. There was no significant difference of PK parameters of midazolam (AUC: 107.74±33.17 and 106.30±56.76 ng/ml·hr, t_1/2:2.6±0.38 and 1.67±0.63 hr, and Cl/F: 1.26±0.42 and 1.46±0.70L/min) and 1-hydroxymidazolam (AUC: 54.22±14.83 and 63.20±18.29 ng/ml· hr), between two phases of placebo and licorice pretreatment. The effect of midazolam on psychomotor tests was not changed after licorice pretreatment. These results suggested that licorice seems not to induce CYP3A4 catalyzing midazolam hydroxylation, and drug interaction of licorice with CYP3A4 substrate drugs are less likely expected in humans.