Linus Pauling Institute, College of Pharmacy, Oregon State University, Corvallis, Oregon (J.L., R.B.v.B.) and UIC Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois (S.B., M.V., E.B., S.-N.C., G.F.P., R.B.v.B.).
Linus Pauling Institute, College of Pharmacy, Oregon State University, Corvallis, Oregon (J.L., R.B.v.B.) and UIC Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois (S.B., M.V., E.B., S.-N.C., G.F.P., R.B.v.B.)
Drug Metab Dispos. 2023 Feb;51(2):199-204. doi: 10.1124/dmd.122.001050. Epub 2022 Nov 3.
Licorice, the roots and rhizomes of 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 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 has been associated with some toxicity. Preclinical studies suggest that 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 extract did not cause any clinically relevant pharmacokinetic drug interactions with four major cytochrome P450 enzymes.
甘草， 的根和根茎，自古以来一直被用作草药、草药辅料和调味剂。最近，甘草提取物作为女性缓解更年期症状的膳食补充剂越来越受欢迎。接触含有高水平甘草酸的甘草产品会导致低钾血症，但独立于这一作用，临床前数据表明，甘草可以抑制某些细胞色素 P450（P450）酶。为了评估甘草与 P450 酶之间是否存在临床相关的药代动力学相互作用，进行了一项使用甘草酸含量<1%的甘草提取物和包含咖啡因、甲苯磺丁脲、阿普唑仑和右美沙芬的鸡尾酒的 1 期临床研究，这些分别是细胞色素 P450 酶 CYP1A2、CYP2C9、CYP3A4/5 和 CYP2D6 的探针底物。从 中鉴定的植物学和化学标准化的根提取物由 14 名绝经和绝经后女性健康参与者每天两次服用，持续 2 周。在补充甘草提取物前后，立即评估每种探针药物的药代动力学。与甘草消耗相比，血清中每种探针底物的平均时间-浓度曲线下面积（AUC）没有显著变化，而咖啡因达到峰值浓度的时间和甲苯磺丁脲的消除半衰期则略有变化。根据基于每个探针底物药物 AUC 变化的美国食品和药物管理局指南，所研究的甘草提取物不应引起任何与 CYP3A4/5、CYP2C9、CYP2D6 或 CYP1A2 相关的临床相关药代动力学相互作用。意义陈述：尽管甘草 被认为是安全的，但它与一些毒性有关。临床前研究表明， 可能通过抑制几种细胞色素 P450 酶引起药代动力学药物相互作用。这项 1 期临床研究通过评估 CYP3A4/5、CYP2C9、CYP2D6 和 CYP1A2 方面的临床相关影响来解决这些问题。这些结果表明，标准化的 提取物不会引起与四种主要细胞色素 P450 酶的任何临床相关的药代动力学药物相互作用。
