Total glucosides from Picrorhiza scrophulariiflora on non-alcoholic steatohepatitis: Analysis of therapeutic effects and the associated pharmacokinetics, tissue distribution, and metabolites

Shuming Li^1,2,3Huan Zhong^4,5,6Zhiqing Tang^4,5,6Xiaolan Mi^2,3Wanyang Sun^4,5,6Rui Liu^2,3Zhaohui Song^2,3Fuming Zhang^2,3Xiaonan Pan^2,3Zhiyong Ji^1*

• ¹School of Chemical Engineering and Technology, Hebei University of Technology, Beichen District, China
• ²Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin, China
• ³National Key Laboratory of Chinese Medicine Modernization, Tianjin, China
• ⁴Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Guangzhou, China
• ⁵International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou, China
• ⁶Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University College of Pharmacy, Guangzhou, China

Background: Picrorhiza scrophulariiflora (PS), prepared from the dried root of Picrorhiza scrophulariiflora Pennell., is a commonly used traditional Chinese medicine recognized for its liver-protective, anti-inflammatory, and anti-oxidative stress properties. The knowledge about the chemistry and pharmacology of PS is increasing with emerging research results, although the material basis of the effects of PS on non-alcoholic steatohepatitis (NASH) and the associated pharmacokinetics, tissue distribution characteristics, and metabolites remains to be elucidated. These findings would provide a further detailed scientific basis for the use of PS in novel drug development and rational clinical applications. 2 Methods: In this study, the chemical composition of PS extract was identified using ultrahigh-performance liquid chromatography/tandem high-resolution mass spectrometry (UPLC-HRMS). The therapeutic effects of different fractions on NASH were subsequently assessed in a mouse model in terms of blood biochemistry and liver pathology results. Next, a reliable and sensitive ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining the pharmacokinetics and tissue distribution of picroside II and picroside I in rats. Finally, UPLC-HRMS was used for metabolite identification. Results: Total glycosides of Picrorhiza scrophulariflora (TGP) was revealed to mainly consist of picroside II and picroside I, and its liver-protective efficacy is about 4–5 times greater than that of silymarin, which highlights its potent in treating NASH by markedly lowering hepatic lipid and serum lipid levels and transaminase activity, thereby enhancing liver health. Post-drug administration, these components were swiftly absorbed and broadly distributed, thereby getting involved in enterohepatic recirculation and crossing the blood-brain barrier. The results from the plasma analysis revealed 18 metabolites that predominantly underwent hydrolysis, glucuronidation, and methylation. Conclusion: TGP is the effective fraction of PS, which demonstrates good liver-protective efficacy, rapid absorption, extensive distribution, specific metabolism, and the ability to cross the blood-brain barrier and participate in enterohepatic circulation. Therefore, TGP has significant biological potential for use in the personalized treatment of NASH and other liver diseases.