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

doi:10.1038/s41401-021-00651-2

	Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule
	Lan, Xiao-fang 1,2; Olaleye, Olajide E.2; Lu, Jun-lan 1,2; Yang, Wei 3; Du, Fei-fei 2; Yang, Jun-ling 2; Cheng, Chen 2; Shi, Yan-hong 2; Wang, Feng-qing 2; Zeng, Xue-shan 2
刊名	ACTA PHARMACOLOGICA SINICA
	2021-04-30
页码	18
关键词	LianhuaQingwen glycyrrhetic acid 24-hydroxyglycyrrhetic acid Gancao-induced pseudoaldosteronism licorice-induced pseudoaldosteronism 11β -hydroxysteroid dehydrogenase 2 COVID-19 colonic microbiota
ISSN号	1671-4083
DOI	10.1038/s41401-021-00651-2
通讯作者	Jia, Wei-wei(weiweijia@simm.ac.cn) ; Li, Chuan(chli@simm.ac.cn)
英文摘要	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 11 beta-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 11 beta-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11 beta-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 mu mol/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 11 beta-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.
资助项目	National Key R&D Program of China[2018YFC1704500] ; National Natural Science Foundation of China[82074273] ; National Natural Science Foundation of China[81603380] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306] ; National Science & Technology Major Project of China 'Key New Drug Creation and Manufacturing Program'[2017ZX09301012-006]
WOS关键词	SYSTEMIC EXPOSURE ; 3-MONOGLUCURONYL-GLYCYRRHETINIC ACID ; XUEBIJING INJECTION ; HERBAL MEDICINE ; GUT MICROBIOTA ; DISPOSITION ; METABOLITE ; TANSHINOL ; IMPACT ; RATS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000646094000002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296519]
专题	中国科学院上海药物研究所
通讯作者	Jia, Wei-wei; Li, Chuan
作者单位	1.Tianjin Univ Tradit Chinese Med, Grad Sch, Tianjin 301617, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China 4.Hebei Yiling Chinese Med Res Inst, Shijiazhuang 050035, Hebei, Peoples R China
推荐引用方式 GB/T 7714	Lan, Xiao-fang,Olaleye, Olajide E.,Lu, Jun-lan,et al. Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule[J]. ACTA PHARMACOLOGICA SINICA,2021:18.
APA	Lan, Xiao-fang.,Olaleye, Olajide E..,Lu, Jun-lan.,Yang, Wei.,Du, Fei-fei.,...&Li, Chuan.(2021).Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.ACTA PHARMACOLOGICA SINICA,18.
MLA	Lan, Xiao-fang,et al."Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule".ACTA PHARMACOLOGICA SINICA (2021):18.