Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents

Abstract

The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered “licorice” in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals’ safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2.

Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .

Keywords:

• AhR
• CYP450
• Glycyrrhiza spp
• herb drug interaction
• PXR

Acknowledgements

The authors sincerely thank Dr. Doanh Tran for his valuable suggestions to improve the overall quality of the manuscript and Ms. Olivia Dale and Ms. Katherine Martin for excellent technical support.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research is supported by the “Holistic Approach for Potential Drug Interactions with Botanical Drugs” funded by the Center for Drug Evaluation and Research, US Food and Drug Administration, grant number HHSF223201810175C.

Notes on contributors

Mona H. Haron

Mona H. Haron, Research Scientist, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi. Pharmacological properties of medicinal plants and their phytochemical constituents with experience in natural product biological evaluation of components derived from botanicals and the naturally occurring microbial communities associated with botanicals for immune function enhancement e.g. Echinacea purpurea and Mushrooms. Also has experience in natural product biological evaluation of neuro-protective activities e.g. Asian ginseng. A special interest in studying the pharmacokinetic herb-drug interactions and safety of medicinal plants and herbal supplements.

Bharathi Avula

Bharathi Avula, Principal Research Scientist, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi. Development and validation of analytical methods using broad range of analytical instrumentation [HPLC/UHPLC with PDA/ELS/RI/EC/FLR /QToF-MS/QqQ-MS detectors, ICP-MS, GC/FID//MS, SFC-UV-MS, Capillary Electrophoresis, Infrared spectrophotometer, Fluorimeter, Polarimeter, UV-Visible spectrophotometer, and TLC densitometer (HPTLC)] that covers a wide spectrum of applications in the field of natural products, biological samples and pharmaceuticals. This expertise involves the qualitative and quantitative characterization of chemical constituents from natural products/biological samples, chemical fingerprinting and standardization of marker or active compounds.

Zulfiqar Ali

Amar G. Chittiboyina, Assistant Director, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi. Broad background in organic chemistry, with specific training and expertise in organic and medicinal chemistry, natural products, and analytical chemistry. Holder of several national, international patents, has authored over 120 peer-reviewed research articles in various scientific journals. His research interests include biogenesis of secondary metabolites; development of synthetic methods for commercial viability; safer and greener ways to produce natural products in gram quantities; synthesis and structure-activity relationships (SAR); implementation of orthogonal methods for the quality assessment of phytochemicals in various matrices; development of non-animal alternative methods in dermatotoxicology; application of computational tools to address the adverse effects such as potential herb-herb and herb-drug interactions associated with phytochemicals. Dr. Chittiboyina received his Ph.D. degree from the National Chemical Laboratory, Pune, India, followed by postdoctoral training at the Department of Medicinal Chemistry, University of Mississippi. Dr. Chittiboyina serves as a consultant for several small biotech companies and well versed in grantsmanship and technology transfer aspects.

Amar G. Chittiboyina

Ikhlas A. Khan, Director and Research Professor of Pharmacognosy at the National Center for Natural Products Research and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi. Main areas of research include phytomedicine, drug discovery, medicinal plants research, analytical fingerprinting for standardization of herbal products, bio-analytical approaches to improvement of product quality and safety, development of analytical methods for phytochemical characterization of biologically active natural products. He has authored/co-authored over 700 research articles. He has been an invited speaker at numerous national and international venues. His work on botanical supplements has helped to shape and lead new developments in academia, industry and government organizations. He has received numerous awards.

Ikhlas A. Khan

Shabana I. Khan, Principal Scientist, and Research Associate Professor of Pharmacognosy, National Center for Natural Products Research and Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi. Research areas include : Pharmacological properties of medicinal plants and their phytochemical constituents; pharmacokinetic herb-drug interactions and safety of medicinal plants and herbal supplements when consumed concomitantly with the clinical drugs for added health benefits in managing chronic diseases.

Jing Li

Zulfiqar Ali is a natural products scientist with over 20 years of research expertise in natural products research. Dr. Ali received his Ph.D. in Chemistry in 2000 from HEJ Research Institute of Chemistry, University of Karachi, Pakistan, and worked as STA/JSPS fellow at Gifu Pharmaceutical University, Japan before joining NCNPR at the University of Mississippi in 2004 as a postdoctoral associate, where he was appointed as Research Scientist in 2011 and promoted to Senior Research Scientist in 2018. Research interests include extraction, isolation, and characterization of chemical/biological markers from medicinal plants and botanicals.

Vivian Wang

Vivian Wang has a MS in ‘Immunology and Microbiology’ and a MS in ‘Information Management’. She is currently working as a Management Analyst in Office of Pharmaceutical Quality, CDER, FDA.

Charles Wu

Charles Wu is a Master Pharmacognosy/Pharmacology Reviewer, and the Botanical Review Team Lead in the Office of Pharmaceutical Quality (OPQ) of the Center for Drug Evaluation and Research (CDER), the United States Food and Drug Administration (FDA). Dr. Wu trained in Clinical Medicine including Traditional Chinese Medicine (TCM) and earned his Ph.D. in medical science from the Medical Center, University of Amsterdam, the Netherlands. Dr. Wu began his career at FDA in 2001 as a biological product reviewer in the Center for Biologics, Evaluation and Research (CBER) and then as a Pharmacology/Toxicology reviewer in CDER. In 2013 Dr. Wu joined the Botanical Review Team (BRT) as a Senior Pharmacologist and promoted to the BRT lead since 2017. He served as the FDA’s Focal Information Contact to the WHO-IRCH (International Regulatory Corporation for Herbal Medicine) since 2019 and became the Steering Group Member and Vice-Chair. Dr. Wu also served as Expert for Regional Consultation of Traditional Medicine to COVID-19 Response in the African Region.

Shabana I. Khan

Jing Li is a Pharmacognosy/CMC Reviewer in the Office of Pharmaceutical Quality (OPQ) of the Center for Drug Evaluation and Research (CDER), the United States Food and Drug Administration (FDA). Since she joined the FDA, she has worked on the review of new drug product applications (INDs/NDAs) both for various complex botanical and conventional medicines. She has also conducted review on combination product for cardiovascular device. As a subject matter expert in pharmacognosy she has been appointed as an FDA expert liaison serving on USP Botanical Dietary Supplements and Herbal Medicines Expert Committee / Botanical Dietary Supplements and Herbal Medicines Nomenclature Committee and Board member of PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, NCI/NIH. Dr. Li holds a B.S. in Pharmacy (Beijing University of Chinese Medicine), M.S. in Pharmacognosy (Chinese Academy of Medical Sciences & Peking Union Medical College), and Ph.D. in Pharmacognosy (National Center for Natural Products Research, School of Pharmacy, the University of Mississippi).