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

文献类型：期刊论文

作者Pan, Lu-lu2,3; Yang, Yong4; Hui, Min1; Wang, Shuo1; Li, Cui-yun5; Zhang, Hong5; Ding, Yan-hua5; Fu, Li1; Diao, Xing-xing2,3; Zhong, Da-fang2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-08-28
页码12
ISSN号1671-4083
关键词forsythin pharmacokinetics drug metabolism drug excretion sulfation glucuronidation organic anion transporter 3
DOI10.1038/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.
WOS关键词UDP-GLUCURONOSYLTRANSFERASE ; MORINIDAZOLE ; FLAVONOIDS ; SULT1A1 ; VAHL
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研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000563600800001
源URL[http://119.78.100.183/handle/2S10ELR8/292487]  
专题新药研究国家重点实验室
通讯作者Ding, Yan-hua; Fu, Li; Diao, Xing-xing; Zhong, Da-fang
作者单位1.Dalian Fusheng Pharmaceut Co Ltd, Dalian 116000, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Suzhou Haike Med Technol Co Ltd, Suzhou 215123, 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.

入库方式： OAI收割

来源：上海药物研究所

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