Abstract：
BACKGROUND: As a representative local medicinal herb produced in China, Vladimiriae Radix (VR) has been proven to exert hepatoprotective and choleretic effects, with particular therapeutic efficacy in cholestatic liver injury (CLI), as demonstrated by the VR extract (VRE). However, the quality markers (Q-markers) of VRE for the treatment of CLI remain unclear.
OBJECTIVE: A new strategy based on the core element of \"efficacy\" was proposed, using a combination of spectrum-effect relationship, pharmacokinetics, and molecular docking methods to select and confirm Q-markers of VRE.
METHODS: First, the HPLC fingerprinting of 10 batches of VRE was studied, and the in vivo pharmacological index of anti-CLI in rats was determined. The spectrum-effect relationship was utilized as a screening method to identify the Q-markers of VRE. Secondly, Q-markers were used as VRE pharmacokinetic markers to measure their concentrations in normal and CLI rat plasma, and to analyze their disposition. Finally, molecular docking was utilized to predict the potential interaction between the identified Q-markers and crucial targets of CLI.
RESULTS: The fingerprints of 10 batches of VRE was established. The in vivo pharmacological evaluation of rats showed that VRE had a significant therapeutic effect on CLI. The spectrum-effect correlation analysis showed that costunolide (COS) and dehydrocostus lactone (DEH) were the Q-markers of VRE anti-CLI. The pharmacokinetic results showed that AUC(0-t), Cmax, CLZ/F, and VZ/F of COS and DEH in CLI rats had significant differences (P < 0.01). They were effectively absorbed into the blood plasma of CLI rats, ensuring ideal bioavailability, and confirming their role as Q-markers. Molecular docking results showed that COS, DEH had good affinity with key targets (FXR, CAR, PXR, MAPK, TGR5, NRF2) for CLI treatment (Binding energy < -4.52 kcal mol-1), further verifying the correctness of Q-marker selection.
CONCLUSIONS: In this study, through the combination of experimental and theoretical approaches from the aspects of pharmacodynamic expression, in vivo process rules, and interaction force prediction, the therapeutic effect of VRE and Q-markers (COS、DEH) were elucidated. Furthermore, a new idea based on the principle of \"efficacy\" was successfully proposed for screening and evaluating Q-markers.
OBJECTIVE: A new strategy based on the core element of \"efficacy\" was proposed, using a combination of spectrum-effect relationship, pharmacokinetics, and molecular docking methods to select and confirm Q-markers of VRE.
METHODS: First, the HPLC fingerprinting of 10 batches of VRE was studied, and the in vivo pharmacological index of anti-CLI in rats was determined. The spectrum-effect relationship was utilized as a screening method to identify the Q-markers of VRE. Secondly, Q-markers were used as VRE pharmacokinetic markers to measure their concentrations in normal and CLI rat plasma, and to analyze their disposition. Finally, molecular docking was utilized to predict the potential interaction between the identified Q-markers and crucial targets of CLI.
RESULTS: The fingerprints of 10 batches of VRE was established. The in vivo pharmacological evaluation of rats showed that VRE had a significant therapeutic effect on CLI. The spectrum-effect correlation analysis showed that costunolide (COS) and dehydrocostus lactone (DEH) were the Q-markers of VRE anti-CLI. The pharmacokinetic results showed that AUC(0-t), Cmax, CLZ/F, and VZ/F of COS and DEH in CLI rats had significant differences (P < 0.01). They were effectively absorbed into the blood plasma of CLI rats, ensuring ideal bioavailability, and confirming their role as Q-markers. Molecular docking results showed that COS, DEH had good affinity with key targets (FXR, CAR, PXR, MAPK, TGR5, NRF2) for CLI treatment (Binding energy < -4.52 kcal mol-1), further verifying the correctness of Q-marker selection.
CONCLUSIONS: In this study, through the combination of experimental and theoretical approaches from the aspects of pharmacodynamic expression, in vivo process rules, and interaction force prediction, the therapeutic effect of VRE and Q-markers (COS、DEH) were elucidated. Furthermore, a new idea based on the principle of \"efficacy\" was successfully proposed for screening and evaluating Q-markers.
摘要：
背景：作为中国生产的代表性地方药材，VladimiriaeRadix（VR）已被证明具有保护肝脏和胆汁的作用，在胆汁淤积性肝损伤（CLI）中具有特殊的治疗效果，如VR提取物（VRE）所示。然而,VRE治疗CLI的质量标记(Q标记)尚不清楚.
目的：提出了一种基于“功效”核心要素的新策略，利用光谱-效应关系的组合，药代动力学，和分子对接方法选择和确认VRE的Q标记。
方法：首先，研究了10批VRE的HPLC指纹图谱，并测定了大鼠体内抗CLI的药理指标。光谱-效应关系被用作鉴定VRE的Q标记的筛选方法。其次,Q标记用作VRE药代动力学标记，以测量其在正常和CLI大鼠血浆中的浓度，分析他们的性格。最后,利用分子对接来预测已鉴定的Q标记与CLI关键靶标之间的潜在相互作用。
结果：建立了10批VRE的指纹图谱。大鼠体内药理评价显示VRE对CLI有显著的治疗作用。谱-效应相关分析表明，谷草内酯（COS）和去氢木霉内酯（DEH）是VRE抗CLI的Q标记。药动学结果显示,AUC(0-t),Cmax,CLZ/F,COS和DEH在CLI大鼠中的VZ/F差异有统计学意义（P<0.01）。它们被有效地吸收到CLI大鼠的血浆中，确保理想的生物利用度，并确认它们作为Q标记的作用。分子对接结果表明,COS,DEH与关键靶标(FXR，汽车,PXR,MAPK,TGR5，NRF2）用于CLI处理（结合能<-4.52kcalmol-1），进一步验证了Q标记选择的正确性。
结论：在这项研究中，通过实验和理论相结合的方法，从药效学表达方面，体内过程规则，和相互作用力预测，阐明了VRE和Q标记（COS，DEH）的治疗效果。此外，成功提出了一种基于“功效”原理的新思想，用于筛选和评估Q标记。
目的：提出了一种基于“功效”核心要素的新策略，利用光谱-效应关系的组合，药代动力学，和分子对接方法选择和确认VRE的Q标记。
方法：首先，研究了10批VRE的HPLC指纹图谱，并测定了大鼠体内抗CLI的药理指标。光谱-效应关系被用作鉴定VRE的Q标记的筛选方法。其次,Q标记用作VRE药代动力学标记，以测量其在正常和CLI大鼠血浆中的浓度，分析他们的性格。最后,利用分子对接来预测已鉴定的Q标记与CLI关键靶标之间的潜在相互作用。
结果：建立了10批VRE的指纹图谱。大鼠体内药理评价显示VRE对CLI有显著的治疗作用。谱-效应相关分析表明，谷草内酯（COS）和去氢木霉内酯（DEH）是VRE抗CLI的Q标记。药动学结果显示,AUC(0-t),Cmax,CLZ/F,COS和DEH在CLI大鼠中的VZ/F差异有统计学意义（P<0.01）。它们被有效地吸收到CLI大鼠的血浆中，确保理想的生物利用度，并确认它们作为Q标记的作用。分子对接结果表明,COS,DEH与关键靶标(FXR，汽车,PXR,MAPK,TGR5，NRF2）用于CLI处理（结合能<-4.52kcalmol-1），进一步验证了Q标记选择的正确性。
结论：在这项研究中，通过实验和理论相结合的方法，从药效学表达方面，体内过程规则，和相互作用力预测，阐明了VRE和Q标记（COS，DEH）的治疗效果。此外，成功提出了一种基于“功效”原理的新思想，用于筛选和评估Q标记。
