Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule

Autor: Chen Cheng, Naixia Zhang, Fang Xu, Yan-Hong Shi, Fengqing Wang, Hong-Tao Wang, Feifei Du, Xue-Shan Zeng, Xuan Yu, Nan-Nan Tian, Chuan Li, Junling Yang, Xiao-Fang Lan, Weiwei Jia, Olajide E. Olaleye, Pei-Wei Liao, Yingfei Li, Wei Yang, Jun-lan Lu
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
LianhuaQingwen
licorice-induced pseudoaldosteronism
Membrane permeability
Metabolite
Phytochemicals
Administration
Oral
Biological Availability
Capsules
24-hydroxyglycyrrhetic acid
Pharmacology
Antiviral Agents
Risk Assessment
Article
Intestinal absorption
Rats
Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
Liddle Syndrome
0302 clinical medicine
Pharmacokinetics
glycyrrhetic acid
11-beta-Hydroxysteroid Dehydrogenase Type 2
Glycyrrhiza
Animals
Humans
Pharmacology (medical)
Glycyrrhizin
Biotransformation
biology
11β-hydroxysteroid dehydrogenase 2
Glycyrrhiza uralensis
Gancao-induced pseudoaldosteronism
COVID-19
General Medicine
biology.organism_classification
COVID-19 Drug Treatment
HEK293 Cells
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Female
Patient Safety
Liquiritigenin
Liquiritin
colonic microbiota
Drugs
Chinese Herbal
Zdroj: Acta Pharmacologica Sinica
ISSN: 1745-7254
1671-4083
DOI: 10.1038/s41401-021-00651-2
Popis: LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11β-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11β-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11β-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01–8.56 μmol/day). Although glycyrrhizin ( 1 ), licorice saponin G2 ( 2 ), and liquiritin/liquiritin apioside ( 21 / 22 ) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid ( 8 ), 24-hydroxyglycyrrhetic acid ( M2 D ; a new Gancao metabolite), and liquiritigenin ( 27 ) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2 D . Circulating 8 and M2 D , having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11β-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2 D . This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.
Databáze: OpenAIRE
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