Yan Ru, Yang Ying, Chen Yijia
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
Zhuhai UM Science & Technology Research Institute, Zhuhai, 519080 China.
Chin Med. 2018 May 2;13:24. doi: 10.1186/s13020-018-0183-z. eCollection 2018.
The modernization and internationalization of Chinese medicines (CMs) are hampered by increasing concerns on the safety and the efficacy. Pharmacokinetic (PK) study is indispensable to establish concentration-activity/toxicity relationship and facilitate target identification and new drug discovery from CMs. To cope with tremendous challenges rooted from chemical complexity of CMs, the classic PK strategies have evolved rapidly from PK study focusing on marker/main drug components to PK-PD correlation study adopting metabolomics approaches to characterize associations between disposition of global drug-related components and host metabolic network shifts. However, the majority of PK studies of CMs have adopted the approaches tailored for western medicines and focused on the systemic exposures of drug-related components, most of which were found to be too low to account for the holistic benefits of CMs. With an area under concentration-time curve- or activity-weighted approach, integral PK attempts to understand the PK-PD relevance with the integrated PK profile of multiple co-existing structural analogs (prototyes/metabolites). Cellular PK-PD complements traditional PK-PD when drug targets localize inside the cells, instead of at the surface of cell membrane or extracellular space. Considering the validated clinical benefits of CMs, reverse pharmacology-based reverse PK strategy was proposed to facilitate target identification and new drug discovery. Recently, gut microbiota have demonstrated multifaceted roles in drug efficacy/toxicity. In traditional oral intake, the presystemic interactions of CMs with gut microbiota seem inevitable, which can contribute to the holistic benefits of CMs through biotransforming CMs components, acting as the peripheral target, and regulating host drug disposition. Hence, we propose a global PK-PD approach which includes the presystemic interaction of CMs with gut microbiota and combines omics with physiologically based pharmacokinetic modeling to offer a comprehensive understanding of the PK-PD relationship of CMs. Moreover, validated clinical benefits of CMs and poor translational potential of animal PK data urge more research efforts in human PK study.
中药的现代化和国际化受到对其安全性和有效性日益增加的关注的阻碍。药代动力学（PK）研究对于建立浓度-活性/毒性关系以及促进从中药中进行靶点识别和新药发现而言不可或缺。为应对源自中药化学复杂性的巨大挑战，经典的PK策略已从专注于标记物/主要药物成分的PK研究迅速发展为采用代谢组学方法的PK-PD相关性研究，以表征全球药物相关成分的处置与宿主代谢网络变化之间的关联。然而，大多数中药的PK研究采用了为西药量身定制的方法，并专注于药物相关成分的全身暴露，其中大多数被发现过低，无法解释中药的整体益处。通过浓度-时间曲线下面积或活性加权方法，整合PK试图通过多种共存结构类似物（原型/代谢物）的整合PK谱来理解PK-PD相关性。当药物靶点位于细胞内而非细胞膜表面或细胞外空间时，细胞PK-PD补充了传统的PK-PD。考虑到中药已验证的临床益处，提出了基于反向药理学的反向PK策略以促进靶点识别和新药发现。最近，肠道微生物群已在药物疗效/毒性方面表现出多方面作用。在传统口服给药中，中药与肠道微生物群的系统前相互作用似乎不可避免，这可通过生物转化中药成分、作为外周靶点以及调节宿主药物处置来促进中药的整体益处。因此，我们提出一种全球PK-PD方法，该方法包括中药与肠道微生物群的系统前相互作用，并将组学与基于生理的药代动力学建模相结合，以全面理解中药的PK-PD关系。此外，中药已验证的临床益处和动物PK数据较差的转化潜力促使在人体PK研究方面加大研究力度。
