Pharmacokinetic mechanisms underlying the detoxification effect of Glycyrrhizae Radix et Rhizoma (Gancao): drug metabolizing enzymes, transporters, and beyond

ABSTRACT

Introduction: Glycyrrhizae Radix et Rhizoma (Gancao in Chinese) is the most frequently used traditional Chinese medicine (TCM) owing to its various pharmacological effects and, more importantly, the synergistic effects that enhance the efficacy and reduce the toxicity of other TCMs.

Areas covered: We reviewed publications, predominantly between 1990 and 2018, that examined pharmacokinetic interactions between Gancao and other TCMs, or the bioactive constituents of these TCMs. This review focuses on the underlying mechanisms and the components responsible for the pharmacokinetic modulation by Gancao.

Expert opinion: In general, the pharmacokinetic effects of Gancao are a result of its constituents such as macromolecules, like proteins, and small molecules, such as saponins and flavonoids. The mechanisms are related to formation of complexes and the influence of these on drug solubility, permeability, distribution, and metabolism. The detoxification effect of a single dose of Gancao is mainly mediated by the suppression of the intestinal absorption of toxic constituents of the co-administered TCMs and is attributable to constituents that form complexes with the toxic compounds and cause them to sediment. In contrast, the detoxification effects of repeated doses of Gancao are mediated mainly via the induction of drug metabolizing enzymes and efflux transporters.

KEYWORDS:

• Drug metabolizing enzymes
• drug transporters
• Gancao protein
• Glycyrrhizae Radix et Rhizoma
• pharmacokinetic interaction
• synergistic function

Article highlights

1. Glycyrrhizae Radix et Rhizoma (Gancao) exerts synergistic effects with other TCMs, increasing their efficacy and/or decreasing their toxicity.

2. The detoxification effect of Gancao is related to its strong impact on the pharmacokinetics of some of the toxic constituents of co-administered TCMs.

3. The detoxification effect of a single dose of Gancao is mainly mediated by the suppression of the intestinal absorption of toxic constituents of the co-administered TCMs and is attributable to constituents that form complexes with the toxic compounds and cause them to sediment.

4. The detoxification effect of repeated doses of Gancao is mediated mainly via the induction of drug metabolizing enzymes and efflux transporters.

5. The formation of sediment and, consequently, the decrease in diester-diterpene alkaloids contents contribute significantly to the detoxification of Aconiti Kusnezoffii Radix (Caowu) and Aconiti Lateralis Radix Praeparata (Fuzi) by Gancao.

6. The detoxification effects of Gancao on Tripterygium wilfordii (Leigongteng) are associated with the induction of drug metabolizing enzymes as well as efflux drug transporters.

7. The formation of complexes between constituents of Gancao, such as saponins, and toxic constituents of Coptidis Rhizoma (Huanglian) reduces the risk of acute toxicity of Huanglian.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the Shanghai natural science foundation (17ZR1430400).