Wilforine, the Q-marker and PK-maker of Tripterygium glycosides tablet: Based on preparation quantitative analysis and PK-PD study

作者：Gao Xue; Xi, Du; An Lijun; Wang Yangyang; Wang Lili; Wu Zengguang; Huang Cong; He Xin^*

来源：Phytomedicine, 2019, 54: 357-364.

DOI：10.1016/j.phymed.2018.03.031

• Wilforine
• Tripterygium glycosides
• Alkaloid
• Q-marker
• PK-maker

Background: The quality standard of Tripterygium glycosides tablet (TGT) by CFDA can not fully reflect the effectiveness and safety. While, Q-marker was proposed to solve the problem of traditional Chinese medicine. PK-marker is mainly used to reflect the material exposure and the influencing factors of Chinese medicine after administration. @@@ Purpose: Based on the study of quantitative analysis, cytotoxicity and pharmacokinetics, this study screened out and confirmed whether wilforine could be served as a potential Q-marker and PK-marker of TGT. @@@ Methods: A sensitive and selective UPLC-MS/MS method was developed and applied to quantitative research of TGT preparation and pharmacokinetics study of TGT. Then, HepG2 cells assay was used to evaluate the cytotoxicity induced by alkaloids in TGT. Then, a PK-PD research was carried out in adjuvant arthritis (AA) rats and control rats after oral administration of TGT, with different dosage and timing. The pharmacokinetic characteristics were determined and calculated by DAS1.0. The pharmacodynamics of TGT was evaluated by the change of paw swelling through one-way ANOVA analysis. @@@ Results: The quality of four alkaloids showed significant difference among four manufacturers, and they were abundant component in TGT from three manufacturers of all. HepG2 cells test revealed that wilforine and wilforgine could induce the cytotoxicity obviously. Pharmacodynamics index suggested that TGT had therapeutic effect on adjuvant arthritis. Thus, the four cases of death occurred in the high dose AA rat group had proven the significant toxicity caused by continuous high dose TGT administration. Furthermore, the result of pharmacokinetic study proved that C-max, and AUC((0-tn)) of wilforine have dose-dependent and time-dependent characteristics. But for wilforgine, there was no indication that there was an accumulation phenomenon in vivo and its plasma concentration showed low exposure. Therefore, it could hardly become the PK-marker of TGT. @@@ Conclusion: Wilforine is proposed as a biologically active and toxic component of TGT that can be served both as Q-marker and PK-marker. The quality, clinical safety, and efficacy of TGT should be evaluated by the quality of wilforine.

• 出版日期2019-2-15
• 单位天津中医药大学