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

Lu-lu Pan1,2, Yong Yang3, Min Hui4, Shuo Wang4, Cui-yun Li5, Hong Zhang5, Yan-hua Ding5, Li Fu4, Xing-xing Diao1,2, Da-fang Zhong1,2
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
Correspondence to: Yan-hua Ding:, Li Fu:, Xing-xing Diao:, Da-fang Zhong:,
DOI: 10.1038/s41401-020-0481-8
Received: 31 March 2020
Accepted: 13 July 2020
Advance online: 28 August 2020


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.
Keywords: forsythin; pharmacokinetics; drug metabolism; drug excretion; sulfation; glucuronidation; organic anion transporter 3

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