Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified

doi:10.1038/s41401-020-0481-8

	Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified
	Pan, Lu-lu 1,2; Yang, Yong 3; Hui, Min 4; Wang, Shuo 4; Li, Cui-yun 5; Zhang, Hong 5; Ding, Yan-hua 5; Fu, Li 4; Diao, Xing-xing 1,2; Zhong, Da-fang 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2020-08-28
页码	12
关键词	forsythin pharmacokinetics drug metabolism drug excretion sulfation glucuronidation organic anion transporter 3
ISSN号	1671-4083
DOI	10.1038/s41401-020-0481-8
通讯作者	Ding, Yan-hua(dingyanhua2003@126.com) ; Fu, Li(2729677386@qq.com) ; Diao, Xing-xing(xxdiao@simm.ac.cn) ; Zhong, Da-fang(dfzhong@simm.ac.cn)
英文摘要	Forsythin extracted fromForsythiae Fructusis widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, similar to 75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.
资助项目	National Natural Science Foundation of China[81521005] ; National Natural Science Foundation of China[81903701] ; National Key Research Project of the Chinese Academy of Sciences[XDA12050306]
WOS关键词	UDP-GLUCURONOSYLTRANSFERASE ; MORINIDAZOLE ; FLAVONOIDS ; SULT1A1 ; VAHL
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000563600800001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292487]
专题	中国科学院上海药物研究所
通讯作者	Ding, Yan-hua; Fu, Li; Diao, Xing-xing; Zhong, Da-fang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Suzhou Haike Med Technol Co Ltd, Suzhou 215123, Peoples R China 4.Dalian Fusheng Pharmaceut Co Ltd, Dalian 116000, Peoples R China 5.First Hosp Jilin Univ, Changchun 130021, Peoples R China
推荐引用方式 GB/T 7714	Pan, Lu-lu,Yang, Yong,Hui, Min,et al. Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified[J]. ACTA PHARMACOLOGICA SINICA,2020:12.
APA	Pan, Lu-lu.,Yang, Yong.,Hui, Min.,Wang, Shuo.,Li, Cui-yun.,...&Zhong, Da-fang.(2020).Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified.ACTA PHARMACOLOGICA SINICA,12.
MLA	Pan, Lu-lu,et al."Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified".ACTA PHARMACOLOGICA SINICA (2020):12.