Abstract
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.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (grant nos. 81521005 and 81903701) and the National Key Research Project of the Chinese Academy of Sciences (grant no. XDA12050306).
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LLP, XXD, LF, and DFZ participated in research design. LLP and YY conducted experiments. MH, SW, and LF contributed new reagents or analytic tools. LLP and YY performed data analysis. YHD, CYL, and HZ participated in clinical trials. LLP, XXD, and DFZ contributed to the writing of the paper.
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Pan, Ll., Yang, Y., Hui, M. et al. Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified. Acta Pharmacol Sin 42, 311–322 (2021). https://doi.org/10.1038/s41401-020-0481-8
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DOI: https://doi.org/10.1038/s41401-020-0481-8
