Pharmacokinetic Interactions of a Licorice Dietary Supplement with Cytochrome P450 Enzymes in Female Participants

Abstract

Licorice, the roots and rhizomes of Glycyrrhiza glabra L., has been used as a medicinal herb, herbal adjuvant, and flavoring agent since ancient times. Recently, licorice extracts have become popular as dietary supplements used by females to alleviate menopausal symptoms. Exposure to licorice products containing high levels of glycyrrhizic acid can cause hypokalemia, but independent from this effect, preclinical data indicate that licorice can inhibit certain cytochrome P450 (P450) enzymes. To evaluate whether clinically relevant pharmacokinetic interactions of licorice with P450 enzymes exist, a phase 1 clinical investigation was carried out using a licorice extract depleted in glycyrrhizic acid (content <1%) and a cocktail containing caffeine, tolbutamide, alprazolam, and dextromethorphan, which are probe substrates for the enzymes CYP1A2, CYP2C9, CYP3A4/5, and CYP2D6, respectively. The botanically authenticated and chemically standardized extract of roots from G. glabra was consumed by 14 healthy menopausal and postmenopausal female participants twice daily for 2 weeks. The pharmacokinetics of each probe drug were evaluated immediately before and after supplementation with the licorice extract. Comparison of the average areas under the time-concentration curves (AUCs) for each probe substrate in serum showed no significant changes from licorice consumption, whereas time to reach peak concentration for caffeine and elimination half-life for tolbutamide showed small changes. According to the US Food and Drug Administration guidance, which is based on changes in the AUC of each probe substrate drug, the investigated licorice extract should not cause any clinically relevant pharmacokinetic interactions with respect to CYP3A4/5, CYP2C9, CYP2D6, or CYP1A2. SIGNIFICANCE STATEMENT: Despite generally-recognized-as-safe status, the licorice species Glycyrrhiza glabra has been associated with some toxicity. Preclinical studies suggest that G. glabra might cause pharmacokinetic drug interactions by inhibiting several cytochrome P450 enzymes. This phase 1 clinical study addressed these concerns by evaluating clinically relevant effects with respect to CYP3A4/5, CYP2C9, CYP2D6, and CYP1A2. These results showed that a standardized G. glabra extract did not cause any clinically relevant pharmacokinetic drug interactions with four major cytochrome P450 enzymes.

Fig. 1.

Clinical study design and schedule of clinical procedures.

Fig. 2.

Average concentration-time curves for four P450 probe substrates pre- and postconsumption of an extract of licorice from G. glabra by 14 female participants for 14 days. The average concentration-time curves for all 14 participants indicate no significant changes in pharmacokinetics for selective probe substrates of CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5. Error bars denote ±S.E.

Fig. 3.

Comparison of individual AUC values for each P450 probe substrate before and after consumption of a G. glabra licorice extract for 14 days. The AUC values of caffeine (CYP1A2 substrate) and tolbutamide (CYP2C9 substrate) showed some pharmacokinetics changes for individual female participants following licorice consumption, but the average value does not suggest significant changes. Error bars denote ±S.E.