Ziqiang Li1, Jia Liu2, Deqin Zhang3, Xi Du4, Lifeng Han5, Chunxiao Lv6, Yanfen Li7, Ruihua Wang8, Baohe Wang9, Yuhong Huang10. 1. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: lzqpharm@126.com. 2. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: liujialiujia1011@163.com. 3. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. Electronic address: deqin123@163.com. 4. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: duxijob@aliyun.com. 5. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. Electronic address: hanlifeng_2008@hotmail.com. 6. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: lvchunxiao1989@163.com. 7. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: liyanfen2008@163.com. 8. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: 13174876122@163.com. 9. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: wbh3423@sina.com. 10. Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Hebei District, Tianjin 300150, China. Electronic address: hyh101@126.com.
Abstract
BACKGROUND: Diabetes is a chronic disease associated with significant morbidity and mortality. Tangzhiqing tablet (TZQ), a Chinese traditional patent medicine, has been in phase 2 clinical trial for the treatment of diabetes mellitus. However, the current quality evaluation of TZQ still remains rather obscure. PURPOSE: The promising quality markers (Q-markers) of TZQ will be sought for its quality assessment and process control based on the qualitative, quantitative and dose-exposure-response analysis. METHODS: The fingerprint analysis of TZQ was carried out through ultra high performance liquid chromatography- quadrupole time-of-flight/ mass spectrometry (UPLC-Q-TOF/MS) assay. Multicomponent quantitative analysis was implemented to the main ingredients of nuciferine, paeoniflorin, salvianolic acid B, hyperoside and rutin in TZQ by means of LC analysis. The dose-exposure-response relationship of TZQ was revealed by a placebo-controlled, 5-way crossover study in healthy Chinese subjects. The potential Q-markers in plasma were determined by a liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method. The therapeutic effect of TZQ was expressed as the glucose-lowering profile. The exposure-response relevance was developed between the concentration of Q-markers and the glucose-lowering effect of TZQ. RESULTS: 46 compounds were identified or tentatively characterized from TZQ. The contents of paeoniflorin, nuciferine, salvianolic acid B, hyperoside and rutin in TZQ were 6.40, 1.75, 1.70, 0.004, and 0.006 mg, respectively. However, salvianolic acid B, hyperoside and rutin could hardly be detected in human plasma under the current LC-MS/MS condition. The exposures of nuciferine and paeoniflorin (AUC0-3, Cmax) were dose-proportionality in human at the studied dosage ranges. The glucose-lowering effect appeared to increase proportionally with increasing TZQ dose in healthy volunteers. A clockwise hysteresis was displayed between the exposure of nuciferine and paeoniflorin and the glucose-lowering effect of TZQ. CONCLUSION:Nuciferine and paeoniflorin were identified as the promising Q-markers of TZQ based on the fingerprint qualitative analysis, multicomponent quantitative analysis and dose-exposure-response analysis. The two Q-markers are meaningful to ensure the quality assessment and process control of TZQ.
RCT Entities:
BACKGROUND:Diabetes is a chronic disease associated with significant morbidity and mortality. Tangzhiqing tablet (TZQ), a Chinese traditional patent medicine, has been in phase 2 clinical trial for the treatment of diabetes mellitus. However, the current quality evaluation of TZQ still remains rather obscure. PURPOSE: The promising quality markers (Q-markers) of TZQ will be sought for its quality assessment and process control based on the qualitative, quantitative and dose-exposure-response analysis. METHODS: The fingerprint analysis of TZQ was carried out through ultra high performance liquid chromatography- quadrupole time-of-flight/ mass spectrometry (UPLC-Q-TOF/MS) assay. Multicomponent quantitative analysis was implemented to the main ingredients of nuciferine, paeoniflorin, salvianolic acid B, hyperoside and rutin in TZQ by means of LC analysis. The dose-exposure-response relationship of TZQ was revealed by a placebo-controlled, 5-way crossover study in healthy Chinese subjects. The potential Q-markers in plasma were determined by a liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method. The therapeutic effect of TZQ was expressed as the glucose-lowering profile. The exposure-response relevance was developed between the concentration of Q-markers and the glucose-lowering effect of TZQ. RESULTS: 46 compounds were identified or tentatively characterized from TZQ. The contents of paeoniflorin, nuciferine, salvianolic acid B, hyperoside and rutin in TZQ were 6.40, 1.75, 1.70, 0.004, and 0.006 mg, respectively. However, salvianolic acid B, hyperoside and rutin could hardly be detected in human plasma under the current LC-MS/MS condition. The exposures of nuciferine and paeoniflorin (AUC0-3, Cmax) were dose-proportionality in human at the studied dosage ranges. The glucose-lowering effect appeared to increase proportionally with increasing TZQ dose in healthy volunteers. A clockwise hysteresis was displayed between the exposure of nuciferine and paeoniflorin and the glucose-lowering effect of TZQ. CONCLUSION:Nuciferine and paeoniflorin were identified as the promising Q-markers of TZQ based on the fingerprint qualitative analysis, multicomponent quantitative analysis and dose-exposure-response analysis. The two Q-markers are meaningful to ensure the quality assessment and process control of TZQ.