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 x h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng x h/ml (34.7%). The GMRs and 90% CI for AUC(0-infinity) and Cmax 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 Cmax 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.
Tu
Jiang-Hua
JH
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110 Xiang-Ya Road, Changsha, Hunan 410078, People's Republic of China
He
Yi-Jing
YJ
Chen
Yao
Y
Fan
Lan
L
Zhang
Wei
W
Tan
Zhi-Rong
ZR
Huang
Yuan-Fei
YF
Guo
Dong
D
Hu
Dong-Li
DL
Wang
Dan
D
Hong-Hao Zhou
D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004311:Double-Blind Method; D019695:Glycyrrhizic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D015394:Molecular Structure; D013810:Therapeutic Equivalency
D000893:Anti-Inflammatory Agents; D019695:Glycyrrhizic Acid; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
J Clin Invest. 1998 Sep 1;102(5):1016-23
9727070
Aliment Pharmacol Ther. 1998 Mar;12(3):199-205
9570253
Antiviral Res. 1989 Jun-Jul;11(5-6):255-61
2572198
Xenobiotica. 2000 Dec;30(12):1131-52
11307970
Regul Toxicol Pharmacol. 2006 Dec;46(3):167-92
16884839
Life Sci. 1998;62(6):571-82
9464470
Cancer Lett. 1999 Oct 18;145(1-2):35-42
10530767
Eur J Clin Pharmacol. 1998 Mar;54(1):53-8
9591931
Clin Pharmacokinet. 2003;42(15):1331-57
14674787
J Pharmacol Exp Ther. 1994 Oct;271(1):549-56
7965755
J Pharm Pharmacol. 1996 Sep;48(9):902-5
8910850
Clin Pharmacol Ther. 1996 May;59(5):491-502
8646820
J Biol Chem. 2000 May 19;275(20):15122-7
10748001
Pharmacogenetics. 1994 Oct;4(5):247-59
7894497
Cancer. 1997 Apr 15;79(8):1494-500
9118029
J Pharmacol Exp Ther. 2006 Mar;316(3):1369-77
16267138
Curr Drug Metab. 2003 Feb;4(1):59-72
12570746
Clin Pharmacol Ther. 2007 Feb;81(2):298-304
17259955
Mol Endocrinol. 2002 May;16(5):977-86
11981033
Annu Rev Pharmacol Toxicol. 2002;42:1-23
11807162
Mol Nutr Food Res. 2006 Nov;50(11):1087-8
17075802
Clin Pharmacol Ther. 1996 Jul;60(1):14-24
8689807
Drug Metab Dispos. 1996 Jun;24(6):634-42
8781778