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

作　　者：Lu-lu Pan Yong Yang Min Hui Shuo Wang Cui-yun Li Hong Zhang Yan-hua Ding Li Fu Xing-xing Diao Da-fang Zhong 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Suzhou Haike Medical Technology Co.,Ltd.,Suzhou 215123,China [4]Dalian Fusheng Pharmaceutical Co.,Ltd.,Dalian 116000,China [5]The First Hospital of Jilin University,Changchun 130021,China

出　　处：《Acta Pharmacologica Sinica》2021年第2期311-322,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(grant nos.81521005 and 81903701);the National Key Research Project of the Chinese Academy of Sciences(grant no.XDA12050306).

摘　　要：Forsythin extracted from Forsythiae Fructus is 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,~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.

关 键 词：FORSYTHIN PHARMACOKINETICS drug metabolism drug excretion SULFATION GLUCURONIDATION organic anion transporter 3 

分 类 号：R96[医药卫生—药理学]