Wang Caihong, Wu Caisheng, Zhang Jinlan, Jin Ying
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
Phytomedicine. 2015 Apr 15;22(4):487-97. doi: 10.1016/j.phymed.2015.02.004. Epub 2015 Mar 11.
Prenylflavonoids are major active components of Epimedii wushanensis herba (EWH). The global pharmacokinetics of prenylflavonoids are unclear, as these compounds yield multiple, often unidentified metabolites.
This study successfully elucidated the pharmacokinetic profiles of EWH extract and five EWH-derived prenylflavonoid monomers in rats.
The study was a comprehensive analysis of metabolic pathways and pharmacokinetic markers.
Major plasma compounds identified after oral administration of EWH-derived prototypes or extract included: (1) prenylflavonoid prototypes, (2) deglycosylated products, and (3) glucuronide conjugates. To select appropriate EWH-derived pharmacokinetic markers, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established to simultaneously monitor 14 major compounds in unhydrolyzed plasma and 10 potential pharmacokinetic markers in hydrolyzed plasma.
The pharmacokinetic profiles indicated that the glucuronide conjugates of icaritin were the principle circulating metabolites and that total icaritin accounted for ∼99% of prenylflavonoid exposure after administration of EWH-derived materials to rats. To further investigate icaritin as a prospective pharmacokinetic marker, correlation analysis was performed between total icaritin and its glucuronide conjugates, and a strong correlation (r > 0.5) was found, indicating that total icaritin content accurately reflected changes in the exposure levels of the glucuronide conjugates over time. Therefore, icaritin is a sufficient pharmacokinetic marker for evaluating dynamic prenylflavonoid exposure levels. Next, a mathematical model was developed based on the prenylflavonoid content of EWH and the exposure levels in rats, using icaritin as the pharmacokinetic marker. This model accurately predicted exposure levels in vivo, with similar predicted vs. experimental area under the curve (AUC)(0-96 h) values for total icaritin (24.1 vs. 32.0 mg/L h).
Icaritin in hydrolyzed plasma can be used as a pharmacokinetic marker to reflect prenylflavonoid exposure levels, as well as the changes over time of its glucuronide conjugates.
异戊烯基黄酮是巫山淫羊藿（EWH）的主要活性成分。异戊烯基黄酮的整体药代动力学尚不清楚，因为这些化合物会产生多种往往无法识别的代谢物。
本研究成功阐明了EWH提取物及5种EWH衍生的异戊烯基黄酮单体在大鼠体内的药代动力学特征。
该研究是对代谢途径和药代动力学标志物的综合分析。
口服EWH衍生的原型物或提取物后，在血浆中鉴定出的主要化合物包括：（1）异戊烯基黄酮原型物，（2）去糖基化产物，以及（3）葡萄糖醛酸苷结合物。为了选择合适的EWH衍生的药代动力学标志物，建立了一种高效液相色谱-串联质谱（HPLC-MS/MS）方法，用于同时监测未水解血浆中的14种主要化合物和水解血浆中的10种潜在药代动力学标志物。
药代动力学特征表明，淫羊藿苷的葡萄糖醛酸苷结合物是主要的循环代谢物，给大鼠服用EWH衍生物质后，总淫羊藿苷占异戊烯基黄酮暴露量的约99%。为了进一步研究淫羊藿苷作为一种潜在的药代动力学标志物，对总淫羊藿苷与其葡萄糖醛酸苷结合物进行了相关性分析，发现两者具有很强的相关性（r>0.5），这表明总淫羊藿苷含量准确反映了葡萄糖醛酸苷结合物暴露水平随时间的变化。因此，淫羊藿苷是评估异戊烯基黄酮动态暴露水平的充分药代动力学标志物。接下来，以淫羊藿苷作为药代动力学标志物，基于EWH中异戊烯基黄酮含量和大鼠体内暴露水平建立了一个数学模型。该模型准确预测了体内暴露水平，总淫羊藿苷的预测曲线下面积（AUC）（0-96小时）值与实验值相似（24.1对32.0mg/L·h）。
水解血浆中的淫羊藿苷可作为药代动力学标志物，以反映异戊烯基黄酮暴露水平及其葡萄糖醛酸苷结合物随时间的变化。
