PBPK模型预测人参皂苷在老年人体内处置和相互作用

The lack of pharmacokinetic data for herbal medicine limits the rational use of herbal medicine in clinic. Understanding the disposition and drug interaction of key herbal compounds herbal medicine will be helpful for the development and the rational use of herbal medicine. Our previous studies revealed that ginsenoside Rg1 and ginsenoside Rb1 are key active components for herbal injections, which contain a component herb Sanqi or Renshen. GRb1 significantly inhibit cellular uptake of estradiol-17β-D-glucuronide mediated by hepatic transporter OATP1B3, and GRg1 was a substrate of the transporters OATP1B3, MRP2, BCRP and BSEP. Cytochrome P450 (CYP2C9、CYP2C19、CYP2A6、CYP2D6、CYP2E1、CYP3A) have low catalytic ability for these ginsenosides. Based on these findings, the applicant hypothesizes that GRb1 would be inhibit the transporter-mediated uptake and/or efflux of GRg1, and influence exposure levels of GRg1. The aim of the current study is to develop physiologically-based pharmacokinetics modeling involving molecular mechanisms (uptake transporters and efflux transporters) for ginsenosides GRb1 and GRg1, and to provide further insight into the pharmacokinetics and disposition of these ginsenosides after intravenous administration to human (especially the elderly) and the herb-herb interaction potential between these ginsenosides in human. The investigation will provide a mechanistic basis for the proper design of clinical studies and the rational use of herbal medicine in clinic.

中药制剂人体药代研究数据的稀缺性制约了其临床合理应用。了解中药成分在体内（尤其老年人）的处置情况和相互作用，对中药制剂的创新发展和合理用药具有积极意义。前期研究表明，GRb1和GRg1是含人参皂苷中药注射液的主要药效物质基础，是该类注射液的研究重点。GRb1和GRg1共同作用于主要肝脏转运体（OATP1B3，MRP2），GRb1表现为抑制剂，而GRg1是底物；人参皂苷基于代谢酶发生抑制或诱导的可能性较小。因此，在转运体分子水平上，申请人推测GRb1通过抑制转运体摄取和/或外排GRg1，而影响GRg1的体内暴露水平。本项目拟借助LC-MS/MS和in silico技术，通过体内和体外手段获取大鼠和正常人体数据支撑，建立GRb1和GRg1基于转运体分子机制的大鼠、正常人体及老年人的PBPK模型，定量预测GRg1和GRb1在人体的处置和相互作用，为优化中药临床研究和安全用药提供新的手段。

Rb1和Rg1是含人参皂苷中药注射液的主要药效物质基础，是该类注射液的研究重点。Rb1和Rg1共同作用于主要肝脏转运体（OATP1B3，MRP2），Rb1表现为抑制剂，而Rg1是底物；人参皂苷基于代谢酶发生抑制或诱导的可能性较小。因此，在转运体分子水平上，申请人推测Rb1通过抑制转运体摄取和/或外排Rg1，而影响Rg1的体内暴露水平。本研究通过体外、体内、PBPK模拟三个方面阐述了含Rb1和Rg1中药注射液在给药后，Rb1对Rg1体内暴露和处置的影响及其机制。体外抑制研究表明，Rb1可以抑制肝脏摄取转运体（人OATP1B3和大鼠Oatp1b2）和人和大鼠的多个外排转运体。再进一步的大鼠在体研究表明，Rb1显著降低Rg1大鼠的肝胆清除率和总清除率显著降低，进而Rg1在大鼠体内的暴露水平C5 min和AUC0-∞显著增加了1.3倍和1.5倍（P < 0.05）。基于以上结果，建立了Rg1基于转运体介导的分子机制PBPK模型，通过抑制模型中转运体活性，可以显著增加了Rg1在模拟体内的暴露水平，也就是说，随着给药剂量的增加，Rb1的剂量也随着增加，进一步增强了对Rg1的抑制作用，提高了Rg1在体内暴露水平。这对于临床合理安全使用含Rb1和Rg1中药注射液具有重要的指导意义。