In vitro and in vivo inhibitory effects of glycyrrhetinic acid on cytochrome P450 3A activity.
The liquorice plant has long been used in both Eastern and Western cultures. Glycyrrhizin is the major triterpenoid saponin in liquorice root, and glycyrrhetinic acid (GA) is its predominant metabolite and a pharmacologically active form of glycyrrhizin. We have assessed the ability of GA to inhibit the enzyme cytochrome P450 3A (CYP3A). A Lineweaver-Burk plot showed that GA was a mixed inhibitor of CYP3A, with an IC₅₀ of 7.25 μmol/l, a K(m) of 4.3 μmol/l and a K(i) of 6.4 μmol/l by non-linear regression analysis. CYP3A activity was also affected by intragastric administration of GA, which resulted in increases in area under the plasma concentration-time curve (AUC)(₀-t) and in apparent elimination half-time (t₁/₂) and significant decreases in body clearance, as well as in the formation of 1-hydroxy-midazolam after intragastric or intravenous administration of midazolam (p < 0.05). An increase in C(max) after intragastric administration (p < 0.05) was also observed. These results suggest the likelihood of an interaction between GA and CYP3A-metabolised drugs in humans and indicate that liquorice root should be used with caution when taken concomitantly with other drugs that interact with CYP3A.
Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
Hai Yun
HY
Li
Wen
W
Xu
Juan
J
Su
Xi
X
Zhang
Li Wei
LW
Hu
Wei Dong
WD
Zhang
D000818:Animals; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; D006034:Glycyrrhetinic Acid; D008874:Midazolam