Potential Drug Interactions Associated with Glycyrrhizin and Glycyrrhetinic Acid
Abstract
Glycyrrhizin (GZ), the major active component of licorice, is a widely used therapeutic in clinical practice. Depending on the disease, treatment may involve long courses of high-dose GZ. Glycyrrhetinic acid (GA), the main active metabolite of GZ, is considered responsible for most of the pharmacological properties of GZ. Both GZ and GA are also utilized to flavor and sweeten foods. Due to this widespread use, potential interactions of GZ and GA with drugs have gained increasing attention. This review covers the known effects of GZ and GA on metabolizing enzymes and efflux transporters. Both GZ and GA may affect cytochrome P450 activity, for example GZ may induce CYP3A activity through activation of the pregnane X receptor (PXR). GZ and GA can influence glucuronidation in both rats and humans. Moreover, 18β-GA is a potent inhibitor of P-glycoprotein, and both GZ and GA inhibit MRP1, MRP2, and BCRP. Therefore, the pharmacokinetics and pharmacodynamics of many drugs may be altered when co-administered with GZ or GA. Caution must be exercised when taking GZ, GA, or related products along with other medications due to these possible drug interactions.
Introduction
Licorice is derived from the roots of Glycyrrhiza uralensis, G. glabra, and G. inflata. It has long been considered one of the most significant Chinese herbal medicines and has been widely used for centuries due to its palatable taste and medicinal properties.
Glycyrrhizin (GZ) is the principal active constituent of licorice, generally occurring in concentrations of 2%–15% depending on the plant species, as well as environmental and climatic conditions. GZ exhibits diverse biochemical and pharmacological activities, including antiallergic, antiviral, immunomodulatory, and anti-inflammatory effects. It also imparts the characteristic sweetness and taste attributed to licorice and is widely used as a sweetening and flavoring agent in foods and tobacco products.
Glycyrrhetinic acid (GA) is the aglycone of GZ and an active metabolite produced after oral ingestion, primarily via the action of colonic microflora. GA exists as two isomeric forms, 18α and 18β, although 18β-GA is generally found in greater amounts. GA contributes to the pharmacological properties of GZ such as antiviral and anti-inflammatory activity, and has also been reported to exhibit cytotoxic effects against ovarian, breast, and hepatocellular carcinoma cells.
Long-term, high-dose usage of GZ and GA, such as in the treatment of chronic hepatitis, results in the possibility of interactions when used with other medications. This review summarizes published data on interactions of GZ and GA with key drug-metabolizing enzymes and efflux transporters.
Interactions of GZ and GA with CYP450s
CYP3A, one of the most important cytochrome P450 isoforms, metabolizes a wide range of xenobiotics, including many therapeutic drugs. Numerous drug interactions result from altered CYP3A activity.
Studies demonstrate that GZ induces CYP3A activity. For example, in clinical trials, administration of GZ reduced midazolam plasma concentrations, suggesting increased metabolism. Similar effects were observed in rat studies where pretreatment with GZ increased the ratio of 1’-hydroxymidazolam to midazolam. Other CYP3A substrates affected by GZ include omeprazole, cyclosporine, and triptolide, all of which demonstrated altered pharmacokinetics following GZ treatment. Evidence suggests this occurs via upregulation of CYP3A gene expression mediated through activation of PXR.
In vitro, GA demonstrates inhibitory effects. GA has been shown to inhibit midazolam hydroxylation and reduce CYP3A-mediated activity in microsomal models. Thus, while GZ induces CYP3A activity in vivo over prolonged use, GA exhibits inhibitory effects in vitro. These observations underscore the importance of experimental context when evaluating drug interactions.
Beyond CYP3A, GZ and GA influence other CYP enzymes. Repeated GZ dosing increased activities of CYP1A2 and CYP2B1, but reduced CYP2E1 and CYP1A1. GA decreased activity of CYP2E1 and inhibited CYP2C9 and CYP2C19 in human liver microsomes, although evidence from in vivo studies is less consistent. These changes must be considered when co-administering GZ or GA with CYP substrates.
Interactions with UGTs
Glucuronidation is a major phase II conjugation pathway involved in elimination of many drugs. GZ and GA significantly affect UGT activity.
Prolonged treatment with GZ in rats increased UGT activity, particularly UGT2, and elevated levels of UDP-GA, the glucuronidation co-factor. GA induced expression of UGT1A8 mRNA in rat liver cells. Thus, after chronic intake, both GZ and GA may induce glucuronidation.
Conversely, in vitro studies reveal inhibitory activity. GA inhibited UGT1A1-mediated glucuronidation of β-estradiol and SN-38, and also inhibited UGT2B7-mediated metabolism of morphine and AZT. Similar findings have been observed with GZ and GA on recombinant human UGT isoforms, including inhibition of UGT1A1, UGT1A3, UGT1A9, and UGT2B7. GA, in particular, is a stronger inhibitor than GZ, likely because GA itself is a UGT substrate while GZ is not.
Interaction with Drug Transporters
P-glycoprotein (P-gp) is an efflux transporter that impacts the absorption and distribution of many drugs. GZ and GA both influence P-gp, although with differing effects. High-dose GZ increased P-gp efflux in cellular assays. Volunteer studies, however, showed no significant alteration in P-gp substrate drug kinetics after several days of GZ administration.
GA, especially the 18β isomer, is a potent inhibitor of P-gp. Studies have shown increased accumulation of daunorubicin, a P-gp substrate, and altered disposition of digoxin in rats co-administered with GA. Docking studies indicate stereoisomerism of GA plays a role in these effects. Thus, GA has the potential to significantly inhibit P-gp function.
GZ and GA also inhibit members of the MRP (multidrug resistance-associated protein) family and BCRP (breast cancer resistance protein). GA inhibited MRP1-mediated efflux, and both GZ and GA inhibited MRP2 and BCRP, reducing transport of their substrates. These inhibitory effects may alter clinical drug disposition.
Drug Interactions with GZ and GA
Because of these enzyme and transporter effects, GZ and GA interact with several drugs.
Co-administration of 18α-GZ enhanced the hypoglycemic effects of glibenclamide, increasing drug bioavailability and significantly lowering plasma glucose in diabetic rats.
When administered with methotrexate, GZ prolonged its half-life and increased bioavailability due to inhibition of MRP-mediated efflux. This increases toxicity risk for MTX.
Co-administration of GZ reduced cyclosporine availability, likely due to GZ induction of P-gp and CYP3A4, which increase CsA metabolism and efflux.
In traditional Chinese medicine, licorice is combined with other herbs such as aconitine, where diammonium glycyrrhizinate increased aconitine absorption and systemic exposure.
GA has also been observed to enhance therapeutic effects of trichostatin A by potentiating its induction of apoptosis in carcinoma cells. GZ delays metabolism of methylprednisolone prodrugs in intestinal contents, prolonging drug activity in models of colitis.
Discussion
GZ exists as two different stereoisomeric forms which metabolize to 18α- and 18β-GA. These isomers exhibit differences in pharmacological activity and potentially in drug interactions. 18α-GA may provide stronger hepatoprotective effects, while 18β-GA is a stronger inhibitor of P-gp.
Metabolism of GZ and GA involves intestinal microflora, hepatic conjugation by UGTs, sulfation, and oxidation. GA is glucuronidated mainly by UGT1A1, 1A3, 2B4, and 2B7, while CYP3A4 is the major enzyme responsible for GA metabolism in human liver. Thus, their pharmacokinetics interlink with CYPs, UGTs, and transporters, explaining broad interaction potential.
Plasma concentrations after oral administration are generally low for GZ but higher for GA, consistent with rapid hydrolysis of GZ. Pharmacokinetic studies confirm enterohepatic circulation and biliary excretion play important roles.
Because GZ and GA influence CYPs, UGTs, and transporters, drugs with narrow therapeutic windows metabolized by these pathways—such as cyclosporine, methotrexate, digoxin, macrolide antibiotics, calcium antagonists, and certain antiretrovirals—should not be co-administered with GZ or GA without careful monitoring.
Conclusion
Glycyrrhizin and glycyrrhetinic acid significantly affect the activities of drug-metabolizing enzymes (CYPs, UGTs) and drug transporters (P-gp, MRPs, BCRP). GZ induces CYP3A through PXR activation and, with prolonged intake, enhances glucuronidation. GA, particularly 18β-GA, acts as a strong inhibitor of P-gp and UGTs. Both compounds potently inhibit MRPs and BCRP. These activities pose substantial risks for drug interactions, especially with medications requiring precise therapeutic control.
Therefore, GZ and GA should be used cautiously in patients under pharmacotherapy, and further studies into the interaction potential of GZ, GA,NSC 167409 and their isomers are warranted.