Ren Hong-Can, Sun Jian-Guo, A Ji-Ye, Gu Sheng-Hua, Shi Jian, Shao Feng, Ai Hua, Zhang Jing-Wei, Peng Ying, Yan Bei, Huang Qing, Liu Lin-Sheng, Sai Yang, Wang Guang-Ji, Yang Cheng-Guang
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
DMPK and Clinical Pharmacology Group, Hutchison MediPharma Ltd., Shanghai, China.
Front Pharmacol. 2022 May 25;13:804377. doi: 10.3389/fphar.2022.804377. eCollection 2022.
The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism.
20(S)-人参皂苷Rh2（Rh2）正作为一种新型抗肿瘤药物进行研发。然而，迄今为止，对于Rh2给药后其去糖基化代谢产物（原人参二醇）（PPD）的动力学了解甚少。本研究的目的是：1）同时表征静脉注射和口服Rh2后Rh2和PPD的药代动力学；2）开发并验证基于机制的药代动力学模型以描述去糖基化动力学；3）预测以PPD形式进入体循环的Rh2的百分比。在静脉注射或口服Rh2后从大鼠采集血浆样本。使用高效液相色谱-质谱法测定血浆中Rh2和PPD的浓度。将Rh2向PPD的转化、其吸收和消除整合到基于机制的药代动力学模型中，以同时描述10mg/kg剂量下Rh2和PPD的药代动力学。20mg/kg剂量Rh2给药后收集的浓度数据用于模型验证。Rh2给药后，PPD表现出高暴露和非典型双峰。该模型很好地描述了异常动力学，并使用外部数据进一步验证。预测静脉注射给药后，总共11%的给药Rh2会转化为PPD并进入体循环，口服Rh2给药后，总共20%的Rh2预计会以PPD形式吸收进入体循环。所开发的模型为定量研究Rh2的去糖基化动力学提供了有用的工具，因此，为未来对具有相似去糖基化代谢的糖苷进行药代动力学研究提供了宝贵的资源。
