Effect of glycyrrhizin on the activity of CYP3A enzyme in humans

Background Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin has been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. Objective To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. Methods Sixteen healthy adult male subjects were enrolled in a two-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered and blood samples were obtained to determine midazolam plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMRs) and 90% confidence intervals (90% CI). Results The geometric mean (geometric coefficient of variation) for the AUC(0-infinity) of midazolam in the placebo group was 196.4 ng.h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng.h/ml (34.7%). The GMRs and 90% CI for AUC(0-infinity) and C(max) of midazolam in the presence/absence of glycyrrhizin were 0.77 (0.70, 0.89) and 0.83 (0.74, 1.01), respectively. The 90% CI for AUC(0-infinity) and C(max) for the GMR of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25. Conclusions Administration of glycyrrhizin resulted in a modest induction of CYP3A that was clinically relevant according to the bioequivalence analysis.