Serum Pharmacochemistry of Traditional Chinese Medicine: Technologies, Strategies and Applications

By Xijun Wang, Aihua Zhang and Hui Sun

Serum Pharmacochemistry of Traditional Chinese Medicine: Technologies, Strategies and Applications provides a valuable and indispensable guide on the latest methods, research advances, and applications in this area. Chapters offer cutting-edge information on pharmacokinetics and pharmacodynamics, analytical chemistry, traditional medicine, natural products, bioinformatics, new technologies, therapeutic applications, and more.

For researchers and students in academia and industry, this book provides a hands-on description of experimental techniques, along with beneficial guidelines to help advance research in the fields of Traditional Chinese Medicine and drug development.

• Provides a valuable guide for practitioners of serum pharmacochemistry of Traditional Chinese Medicine, along with insights to its current use and future applications
• Edited and written by leading scientists at the forefront of this research
• Presents well written chapters that include an introduction, description of the method, and identification of chemical constituents, with applications and references to the latest research and literature

• Language: English
• Publisher: Academic Press
• Release date: Dec 27, 2016
• ISBN: 9780128111482

Book preview

Serum Pharmacochemistry of Traditional Chinese Medicine

Technologies, Strategies and Applications

Editor

Xijun Wang

Associate Editors

Aihua Zhang

Hui Sun

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface

Chapter 1. Traditional Chinese Medicine: Current State, Challenges, and Applications

1. Current State

2. Application of TCM

3. The Coming Era of Precision Medicine: What Can We Learn From Chinese Medicine?

4. The Challenges of TCM

5. Future Perspective

Chapter 2. Serum Pharmacochemistry of Traditional Chinese Medicine: Historical Development and Strategies

1. Historical Development of Serum Pharmacochemistry of Traditional Chinese Medicine

2. Theoretical Foundation and Research Category of SPT

3. SPT Techniques

4. Application and Future Perspectives of SPT

5. Conclusion

Chapter 3. Integrated Serum Pharmacochemistry of TCM and Metabolomics Strategies for Innovative Drug Discovery

1. Introduction

2. Metabolomics in Efficacy Evaluation of Formulae

3. Integrated Serum Pharmacochemistry of TCM With Metabolomics

4. Conclusion

Chapter 4. UPLC/MS and Its Potential in Traditional Chinese Medicine Development

1. Introduction

2. Potential Power of UHPLC-MS

3. UHPLC-MS Approach in TCM

4. Identification of Chemical Constituents in TCM Samples

5. Qualitative and Quantitative Analysis of TCM

6. Pharmacokinetics

7. UHPLC-MS-Based Metabolite Identification

8. Metabolomics Application

9. Quality Control of TCM

10. Pharmacological Studies

11. Conclusions and Future Perspective

Chapter 5. Analytical Characterization of Yin-Chen-Hao-Tang by Serum Pharmacochemistry of TCM

1. Introduction

2. Experimental

3. Results and Discussions

4. Conclusion

Chapter 6. Pharmacokinetic Strategy for Screening the Effective Components From YCHT

1. Introduction

2. Experimental

3. Results

4. Discussion

5. Conclusion

Chapter 7. Synergism Effects of Active Ingredients From YCHT

1. Introduction

2. Materials and Methods

3. Results

4. Discussion

5. Conclusion

Chapter 8. Serum Pharmacochemistry of TCM for Screening the Active Ingredients From Wen-Xin Formulae

1. Introduction

2. Experimental

3. Results and Discussion

4. Conclusion

Chapter 9. Characterization and Pharmacokinetic Study of Multiple Constituents From Shengmai San

1. Introduction

2. Experimental

3. Results and Discussion

4. Conclusion

Chapter 10. Multivariate Data Processing Tools to Screen the Active Ingredients From Kai-Xin-San

1. Introduction

2. Material and Methods

3. Results and Discussion

4. Conclusion

Chapter 11. Serum Pharmacochemistry of TCM for Determining the Active Ingredients of Shuanghuanglian Formulae

1. Introduction

2. Material and Methods

3. Results

4. Discussion

5. Conclusion

Chapter 12. Pharmacokinetic–Pharmacodynamic Study of Zhi Zhu Wan

1. Introduction

2. Experimental

3. Results

4. Discussion

5. Conclusion

Chapter 13. Identification of the Absorbed Components of Shaoyao-Gancao Decoction

1. Introduction

2. Materials and Methods

3. Results and Discussion

4. Conclusions

Chapter 14. Rapid Analysis of Multiple Constituents of Suanzaoren Decoction by UPLC-MS

1. Introduction

2. Experimental

3. Results and Discussion

4. Conclusion

Chapter 15. UPLC-MS Analysis of the Chemical Constituents of Liuwei Dihuang Wan

1. Introduction

2. Material and Methods

3. Results and Discussion

4. Conclusion

Chapter 16. Multivariate Data Analysis for Rapid Identification of Chemical Constituents of Simiao Wan

1. Introduction

2. Material and Methods

3. Results and Discussion

4. Conclusion

Chapter 17. Time-Course Study of Multicomponents After Oral Administration of Stemonae Radix

1. Introduction

2. Experimental

3. Results

4. Discussion

5. Conclusion

Chapter 18. Global Characterization of Chemical Constituents of Phellodendri amurensis Cortex

1. Introduction

2. Material and Methods

3. Results and Discussion

4. Conclusion

Chapter 19. Comparative Analysis of Chemical Constituents of Phellodendri amurensis Cortex and Zhibai Dihuang Pill

1. Introduction

2. Materials and Methods

3. Results and Discussion

4. Conclusion

Chapter 20. UPLC-MS Determining the Active Ingredients of Herbal Fructus Corni In Vivo

1. Introduction

2. Material and Methods

3. Results and Discussion

4. Conclusion

Chapter 21. Serum Pharmacochemistry of TCM Screening the Bioactive Components From Moutan Cortex

1. Introduction

2. Material and Methods

3. Results

4. Discussion

5. Conclusion

Chapter 22. Rapid Analysis of Constituents and Metabolites From Extracts of Acanthopanax senticosus Harms Leaf

1. Introduction

2. Experimental

3. Results and Discussion

4. Conclusion

Chapter 23. Systematic Characterization of the Absorbed Components of Acanthopanax senticosus Stem

1. Introduction

2. Experimental

3. Results and Discussion

4. Conclusion

Chapter 24. Identification of the Absorbed Constituents of Schisandra Lignans by Serum Pharmacochemistry of TCM

1. Introduction

2. Experimental

3. Results

4. Discussion

5. Conclusion

Index

Copyright

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List of Contributors

All contributors are located at: National TCM Key Laboratory of Serum Pharmacochemistry, Laboratory of Metabolomics and Chinmedomics, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China

Tianwei Dong

Wei Dong

Ying Han

Guozheng Jiao

Chang Liu

Jianhua Liu

Yuan Li

Hui Shi

Hui Sun

Wenjun Sun

Yunlong Tan

Ping Wang

Qinqin Wang

Xijun Wang

Yuying Wang

Wenfeng Wei

Fangfang Wu

Bo Yang

Guangli Yan

Quanwei Yin

Aihua Zhang

Fangmei Zhang

He Zhang

Ying Zhang

Yingzhi Zhang

Xiaohang Zhou

Ying Zhou

Di Zou

Preface

Serum pharmacochemistry of traditional Chinese medicine (SPT) is the theory and research method for identifying the efficacy material basis from serum containing active constituents after oral traditional Chinese medicine (TCM) formulas (prescription). Its theory and research method were designed mainly based on the formation of the active ingredients from TCM and their effects. Chinese medicine is administered in the form of formulas. Many ingredients in TCM formulas can only produce the pharmacological effects after absorption into the bloodstream and then become active ingredients by structure transformation-produced metabolites, eventually becoming an effective form. The active substance in the blood as a medium must be delivered to the target before initiating its pharmacological effects. Therefore serum after administration of TCM is the real preparation, including prototype components, metabolites, and physiologically active substances, and the components contained in the serum are the direct effect in vivo substances. The efficacy material basis of TCM needs to be discovered, analyzed, and isolated from the serum after oral formulas. Thus Professor Xijun Wang has proposed the research design of SPT that has identified the effective substance basis from serum-containing drug after oral TCM formulas. It not only reflects the effect of the drug on the body but also reflects the drug interaction, which supplants the traditional research models for TCM that only focus on what ingredients are contained in TCM and what ingredients can display pharmacological activity in in vitro experiments, but not really clarifying the efficacy material basis of TCM. The SPT method is a big step forward in realizing the direct effect of substances in vivo after oral TCM formulas.

The proposed SPT approach has been successfully applied in the characterization of multicomponent in vivo after oral formulas, and further analyzes the correlation between the exogenous constituents in vivo and clinical efficacy, clarifying the pharmacodynamic material basis of more than 100 relevant formulas such as Yinchenhao Tang, Liuweidihuang Wan, Shengmai San, Kaixin San, Zhizhu Wan, Simiao Wan, etc. Therefore we have improved the methods of SPT and summarized its system theory. SPT has defined as isolated and identified the efficacy material basis from serum containing active constituents after oral formulas, clarifying metabolism and pharmacokinetics of the direct effect substances in vivo, and reflecting the in vivo state of therapeutic substance of formulas, effectively guiding innovative drug design. For the Establishment and Implementation of Serum Pharmacochemistry of TCM, we won the 2002 National Science and Technology Progress Second Award of China. Developed over 30  years, SPT has become a universal theory to guide the discovery of efficacy material and common key technologies that are widely used in efficacy and safety studies on TCM quality. Under the guidance of the theory and methods of SPT, we have discovered more than 600 lead compounds and 10 new drugs. Thus, in this book, we have systematically arranged the theory and research method of SPT, and combined these with the results of our research work since 2010, to try to provide a reference for international scientists, researchers, and students who engage in research of natural medicine or traditional medicine. We sincerely expect our work to promote the technological advances in traditional medical research, especially in the academic progress and international development of TCM.

Xijun Wang

Professor, PhD

General Director

National TCM Key Laboratory of Serum Pharmacochemistry

Sino-US Chinmedomics Technology Cooperation Center

Chinmedomics Research Center of TCM State Administration

Laboratory of Metabolomics

Heilongjiang University of Chinese Medicine

Heping Road No. 24, Harbin 150040, China

Tel. and Fax: [phone]

Email: [e-mail]; [e-mail]

Chapter 1

Traditional Chinese Medicine

Current State, Challenges, and Applications

Xijun Wang, Aihua Zhang, Hui Sun, Guangli Yan, Ping Wang, and Ying Han

Abstract

The 2015 Nobel Prize for Physiology or Medicine, won by pharmacologist Youyou Tu, was the first science Nobel Prize awarded to a China-based scientist. Tu's discovery of artemisinin—a key antimalarial drug credited with saving millions of lives—was rooted in ancient Chinese herbal medicine. It has brought traditional Chinese medicine (TCM) to the forefront of the global research community's attention. Globally, scientists are frequently looking for therapeutic agents from TCM, which is a rich source of potential leads for drug development. TCM, which is an essential part of the health care system in most Asian countries, relies on natural products and has been playing a very important role in health protection and disease control for thousands of years. TCM therapeutic efficacy, usually attributed to the synergistic property of multiple herbs and constituents, has advocated combinatorial therapeutic strategies called formulae that improve efficacy through hitting multiple targets Based on syndromes and patient characteristics, and guided by the TCM theory, formulae are designed to contain a combination of various kinds of crude drugs that, when combined, generally assume that a synergism of all ingredients will bring about the maximum of therapeutic efficacy.

Keywords

Effective material basis; Multiherb; Precision medicine; TCM; TCM formulae

1. Current State

The 2015 Nobel Prize for Physiology or Medicine, won by pharmacologist Youyou Tu, was the first science Nobel Prize awarded to a China-based scientist. Tu’s discovery of artemisinin—a key antimalarial drug credited with saving millions of lives—was rooted in ancient Chinese herbal medicine (Tu, 2011). It has brought traditional Chinese medicine (TCM) to the forefront of the global research community’s attention. Globally, scientists are frequently looking for therapeutic agents from TCM, which is a rich source of potential leads for drug development. Shifting the current drug discovery tide from finding new drugs to screening natural products may be helpful for overcoming the more investment, fewer drugs challenge. The World Health Organization estimates that 80% of the world’s population relies on herbs for their primary health care needs (Zhang et al., 2013). TCM, which is an essential part of the health care system in most Asian countries, relies on natural products and has been playing a very important role in health protection and disease control for thousands of years. TCM therapeutic efficacy, usually attributed to the synergistic property of multiple herbs and constituents, has advocated combinatorial therapeutic strategies called formulae that improve efficacy through hitting multiple targets. Based on syndromes and patient characteristics, and guided by the TCM theory, formulae are designed to contain a combination of various kinds of crude drugs that, when combined, generally assume that a synergism of all ingredients will bring about the maximum of therapeutic efficacy (Fig. 1.1A).

Typically, according to the principle of TCM, the herbal formulae include four elements: the monarch (Jun), minister (Chen), assistant (Zuo), and servant (Shi). In TCM formulae, monarch aims at the cardinal pathological symptom of a disease. Minister assists monarch to treat other secondary symptoms, if applicable. Assistant and servant mainly coordinate the formulae, facilitate performances of monarch and minister, and decrease their side effects. They work together harmoniously to achieve an ideal therapeutic outcome. However, the direct effect substances in vivo are poorly understood and thus hamper the modernization of TCM; they must be addressed using modern analytical techniques coupled with innovative methodology. Some researchers have made good attempts in this area using approaches to identify the multicomponents from herb medicines (Song et al., 2016; Wang et al., 2016). These studies can be considered a useful pilot trial in the effort to evaluate traditional formulae on a larger scale. Furthermore, these observations indicate that traditional formulae usually require multiple components to exert their effects, possibly laying the foundation for promising new schemes and patterns of advancing drug development from active constituents of formulae toward better therapeutic effects.

Figure 1.1  The Characteristics of Traditional Chinese Medicine (TCM) on Ancient Chinese Philosophy.

(A) TCM practitioners often prescribe a combination of herbs called formulae that work together harmoniously to achieve an ideal therapeutic outcome. (B) Formulae consisting of multiherbs possess multicomponent and multitarget characteristics.

TCM, one of the oldest phytomedicine systems of health care, has been used in Asian countries such as China, Japan, and Korea for thousands of years. Based on its long history of clinical use and wide-ranging effects in the treatment of numerous diseases, especially chronic diseases, TCM is increasingly accepted and used by billions of people around the world. For improving health, practitioners advocated combinatorial therapeutic strategies based on overall symptoms and signs of syndrome and often prescribe formulae that work together harmoniously to achieve ideally therapeutic effects. A single herb already contains thousands of compounds; formulae consisting of multiherbs possess multicomponent and multitarget characteristics (Fig. 1.1B). Compared with chemical drugs, TCM has multicomponent, multitarget, and multipathway characteristics and possesses unparalleled advantages when faced with miscellaneous diseases. This means that the efficacy of TCM depends on the combined action of multiple herbs because it usually contains a lot of ingredients and exerts synergistic therapeutic efficacies. However, this can cause many difficulties in the search for effective substances from TCM.

2. Application of TCM

TCM is based on ancient Chinese philosophy. Its characteristics include yin yang theories, five element concepts, subjective diagnostic methods, holism, treatment of differential syndromes, dynamic functional aspects, etc. TCM treatment with therapeutic strategies in a holistic fashion is based on overall symptoms and signs of differential syndromes and, from a nonlinear point of view, concerns disease from various dynamic functional aspects. It focuses on the patient rather than the disease, promoting enhanced quality of life. TCM often uses formulae that comprise several types of crude herbs tailored to an individual’s condition based on subjective diagnosis methods. TCM advocates combinatory therapeutic strategies by formulae, in which one represents the key component and others serve as adjuvants to assist the effects or facilitate the delivery of the key components (Wang et al., 2013). According to TCM theory, formulae include four elements: the monarch (which plays the most important role in the formulae), the minister (which increases the effectiveness of the monarch herb), the assistant (which helps the monarch and minister herbs reach their target positions), and the servant (which can reduce the adverse effects and/or increase the potency of the whole formulae).

Because of a long cultural heritage and rich natural resources, a wealth of knowledge of traditional medicine has been accumulated in China. At least 11,146 plant species, 1581 animal species, and 80 minerals and substances, ranging from precious stones to mineralized fossils, are used as TCM medicines (Liu et al., 2013). Typically, formulae, which consist of several herbs, would comprise hundreds of compounds as a complex system that contains lots of components with diversities in chemical structures, biological activities, and interactions among compounds, and the content for each component varies greatly. Many Chinese therapeutic herbs traditionally used in the cotreatment but not monotreatment series demonstrate significantly better pharmacological effects, because the combination application of TCM can achieve a synergistic interaction capable of yielding a sufficient effect at low doses. Tremendous progress has been made in the past few years; however, cancer, diabetes, and other complex diseases may limit the performance of the single-target-drug paradigm. Meanwhile, some researchers found that a combination of multiple compounds rather than using a single compound could achieve increased effectiveness (Zhang et al., 2014). With the wave of returning to nature, people from all over the world are becoming increasingly interested in the magical effects of the formulae. Like almost all other traditional medicines, at present formulae are still being practiced in their original form and although effective in treating many conditions, they lack necessary scientific research. The lack of a comprehensive understanding of the relationship between syndrome and formulae makes it difficult to advance TCM from modern sciences, which stagnates the development of TCM. For TCM to be modernized, it is critical to use modern tools to determine its mechanism of action.

3. The Coming Era of Precision Medicine: What Can We Learn From Chinese Medicine?

President Obama in the State of the Union Address announced the launch of a new Precision Medicine Initiative (Fox, 2015). Precision medicine promises to match the right patient with the right diagnosis, the right treatment, in the right amount. The era of personalized precision medicine is about to emerge. The personalized treatment of TCM is consistent with the ideology of precision medicine. Obviously, compared with modern medicine, TCM leans toward precision, reflecting personalized medicine, because it has a complete theoretical system and a mature method for the diagnosis of an individual’s condition. After the development and improvement of TCM by ancient physicians, TCM formed the coordination of theory and practice of precise diagnosis and precise treatment in a dynamic state. Chinese medicine adjusts the physique of patients by way of syndrome differentiation, something that Western medicine cannot do. TCM treatment in a holistic fashion is based on overall symptoms and signs of syndromes, and concerns disease from various dynamic functional aspects (Liu et al., 2016). It focuses on the patient rather than the disease, promoting and enhancing the quality of life. TCM often uses formulae that are comprised of several crude herbs tailored to an individual’s condition based on subjective diagnosis. Interestingly, to improve clinical efficacy, formulae variation with syndrome and formulae corresponding syndrome have practical significance for the precise use of formulae and accurate diagnosis of syndromes. The patient’s response and treatment could be closely monitored with direct or surrogate biomarkers. Formulae efficacy is important for the discovery of effective material basis in TCM. Researchers have therefore made an effort to innovate TCM research methods aimed at solving the effective material basis of TCM formulae.

4. The Challenges of TCM

In the 21st century, TCM is facing the challenges of internationalization of economic globalization. The biggest obstacle for TCM is that most countries of the world are excluded from formal medicine, and there is no statutory status to protect the existence of alternative medicine. TCM in the European market at present is mostly in the form of food and health products; this not only reduces the status of TCM in the international arena, but also impacts the international share of the herbal medicine market. Meanwhile, since joining the World Trade Organization, with the overall economic development of the pharmaceutical market, the domestic market for TCM has also encountered the impact of foreign medicine. How TCM can stably occupy the domestic market will become a major problem in modern medicine. Low exports and weak competitiveness in the market is mainly caused by unstable efficacy, unclear pharmacodynamic material basis, lack of international quality standards, unclear toxicity, etc., but the key factor is that the effective material basis is unclear. Once the material basis is clear, we can clarify the efficacy, develop the internationally recognized quality standards to improve the process and content of active substances, reduce the unwanted or toxic substances, etc. Therefore the characterization of effective material basis has become a bottleneck, which restricts the development of TCM. Since TCM knowledge and techniques are mostly clinical expertise inherited and developed from ancient TCM physicians and books, many of which do not have standardized and scientific procedures and criteria, TCM is impeded from disseminating globally. It is necessary to introduce new strategies and technologies into TCM for its standardization and globalization.

5. Future Perspective

With economic development and rising living standards, people’s concepts of health and way of life have undergone great changes. Disease prevention through TCM, which has a wealth of clinical experience, will become more important in life sciences. The key issue for TCM is how to use the modern technology to discover the effective material basis. The current tide may be turning back to nature in the search for new drug candidates. Millennia-old Chinese medicine treats disease with many combination therapies involving ingredients used in clinic practice. Increasing evidence has demonstrated that the clinical use of combinatorial intervention in TCM achieves synergistic interactions that are capable of producing a sufficient effect at low doses. Of note, it beneficially accounts for the popular view that TCM usually takes multicomponents to exert their action. It is hoped that these studies will lay the appropriate foundation for dissecting the novel synergism of multicomponents from TCM to improve therapeutic effects and offer bright prospects for the control of complex diseases in a synergistic manner. It may provide a promising strategy in natural products and new combination medicine patterns derived from TCM.

References

Fox J.L. Obama catapults patient-empowered precision medicine. Nat. Biotechnol. 2015;33(4):325.

Liu X, Wu W.Y, Jiang B.H, Yang M, Guo D.A. Pharmacological tools for the development of traditional Chinese medicine. Trends Pharmacol. Sci. 2013;34(11):620–628.

Liu J, Mu J, Zheng C, Chen X, Guo Z, Huang C, Fu Y, Tian G, Shang H, Wang Y. Systems-pharmacology dissection of traditional Chinese medicine compound saffron formula reveals multi-scale treatment strategy for cardiovascular diseases. Sci. Rep. 2016;6:19809.

Song H.P, Wu S.Q, Hao H, Chen J, Lu J, Xu X, Li P, Yang H. A chemical family-based strategy for uncovering hidden bioactive molecules and multicomponent interactions in herbal medicines. Sci. Rep. 2016;6:23840.

Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 2011;17(10):1217–1220.

Wang X, Zhang A, Wang P, Sun H, Wu G, Sun W, Lv H, Jiao G, Xu H, Yuan Y, Liu L, Zou D, Wu Z, Han Y, Yan G, Dong W, Wu F, Dong T, Yu Y, Zhang S, Wu X, Tong X, Meng X. Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies. Mol. Cell Proteom. 2013;12(5):1226–1238.

Wang X, Zhang A, Zhou X, Liu Q, Nan Y, Guan Y, Kong L, Han Y, Sun H, Yan G. An integrated chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. Sci. Rep. 2016;6:18997.

Zhang A, Sun H, Wang X. Recent advances in natural products from plants for treatment of liver diseases. Eur. J. Med. Chem. 2013;63:570–577.

Zhang A, Sun H, Wang X. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytother. Res. 2014;28(4):526–533.

Chapter 2

Serum Pharmacochemistry of Traditional Chinese Medicine

Historical Development and Strategies

Xijun Wang, Aihua Zhang, Hui Sun, and Guangli Yan

Abstract

Serum pharmacochemistry is a new discipline that has rapidly developed over the years, but its successful practice can be traced back to the invention of sulfonamides by Gerhard Domagk. German scientists synthesized a drug called prontosil in the 1930s, but it did not show the bactericidal effect in vitro. Domagk found that prontosil did not exert its effect in vitro, while injection in animal models was effective. His further research found that prontosil produced sulfonamides by an in vivo metabolism, and this metabolite had a bactericidal effect. This practice should have been an important development in drug in vivo research, but for a long period of time, regrettably a system methodology was not established.

Keywords

Efficacy material basis; Multicomponents; Pattern-recognition approaches; Principal component analysis; Serum pharmacochemistry; SPT; TCM

1. Historical Development of Serum Pharmacochemistry of Traditional Chinese Medicine

Serum pharmacochemistry is a new discipline that has rapidly developed over the years, but its successful practice can be traced back to the invention of sulfonamides by Gerhard Domagk. German scientists synthesized a drug called prontosil in the 1930s, but it did not show the bactericidal effect in vitro. Domagk found that prontosil did not exert its effect in vitro, while injection in animal models was effective. His further research found that prontosil produced sulfonamides by an in vivo metabolism, and this metabolite had a bactericidal effect (Jeśman et al., 2011). As a result of the invention of sulfonamides, Domagk received the 1939 Nobel Prize (Sulek et al., 1968). This practice should have been an important development in drug in vivo research, but for a long period of time, regrettably a system methodology was not established. In the late 1980s the Japanese scholar Shikano Mihiro published a paper Components of Chinese traditional prescription ʻKANZOFUSITO’ in rat portal blood after oral administration (Kano et al., 1989). At the same time, Japanese scholar Shinichi Tashiro raised the idea that traditional medicine to produce biologically active ingredients may be done with products through bacterial metabolism. Thus they initially proposed the concept of serum pharmacology and serum pharmacochemistry. In 1994, Shikano Mihiro, Xijun Wang, Shasha Wang, etc. published papers on the pharmacokinetics of in vivo ingredients of Yin-Chen-Hao-Tang, an active ingredient in serum and bile after oral Polygalae Radix extract, etc. (Wang et al., 1994). They actually applied serum pharmacochemistry to practices. Since then, Professor Xijun Wang conducted a number of practices of serum pharmacochemistry on traditional Chinese medicine (TCM), and then in 1997 formally proposed the concept and theory of serum pharmacochemistry of traditional Chinese medicine (SPT). In 2011, he published an article on Studies on serum pharmacochemistry on traditional Chinese medicine (Wang, 2002), and accomplished system research on Establishment and implementation of serum-pharmacochemistry of TCM.

For the establishment and implementation of SPT, the authors won the 2002 National Science and Technology Progress Second Award, China, which confirmed the technical specifications of theory and method on SPT. It was preliminarily defined as isolated and identified the efficacy material basis from serum containing active constituents after oral formulae, clarifying metabolism and pharmacokinetics of the direct effect substances in vivo, and reflecting the in vivo state of the therapeutic substance of formulae, effectively guiding innovative drug design. The proposed strategy of SPT is shown in Fig. 2.1. Based on the comprehensive analysis of the efficacy material basis from blood samples, the compatibility law is scientifically annotated through the dynamic interaction of in vivo ingredients. Research on the components in the serum could be an effective approach to identify the effective substances. SPT can reflect drug action, absorption, distribution, and interaction in the body. In the standardization process of TCM, determining the efficacy material basis is a crucial step, and discovering the in vivo process is the key to the normalization of drugs. For more than 20  years, it has become the key technology for analyzing and screening in vivo active ingredients of TCM (Yan et al., 2015). It provides methodology for the discovery of active constituents in vivo from TCM, solving its efficacy and effectiveness.

Figure 2.1  The proposed strategy of serum pharmacochemistry of traditional Chinese medicine (TCM).

2. Theoretical Foundation and Research Category of SPT

TCM has its own unique medical system with the significant characteristics of pursuing an overall therapeutic effect with a multitarget treatment. It consists of multiple medicinal plants (called formulae) that can regulate balance and homeostasis of the body in a holistic fashion, and exert synergistic effects via the interaction of ingredients in the formulae. Because of the complexity of the chemical compositions and many endogenous intervening substances, it is a challenge to identify the chemical constituents and metabolites related to TCM. Traditional research models for TCM only focus on the ingredients contained in TCM and what ingredients can display pharmacological activity in in vitro experiments, but do not really clarify the efficacy material basis of TCM. Conventional bioactivity method-guided extraction and separation fails to reflect the overall efficacy of formulae. Because it has a low collecting rate, is activity losing, only structure elucidation, it does not reflect biotransformation and express the drug interaction in the formulae in vivo. This approach ignores the fact that in the vast majority of cases clinical administration of TCM is through oral administration. After being metabolized by the gastrointestinal tract and liver, the components that finally reach the blood are usually not the original drug ingredients. There are also metabolism ingredients. Many ingredients in TCM can only produce an effect after absorption into the bloodstream. The blood-contained ingredients may be the substances that play a direct role in the body. The active substance in the blood as a medium must be delivered to the target and result in pharmacological effects. Thus serum after administration of TCM is the real preparation, including prototype components, metabolites, and physiologically active substances, and the components contained in the serum are the direct effect in vivo substances. Therefore the efficacy material basis of TCM must be carried out in serum after administration of TCM. The research category of SPT should include the following aspects: (1) composition analysis and quality evaluation of TCM sample; (2) selection of experimental animals; (3) dosing regimen; (4) sampling time and mode; (5) preparation of serum samples containing drugs; (6) analytical methods of serum samples; (7) component preparation in serum sample; (8) correlation analysis of components in serum sample with the