Research,Status,of,Serum,Pharmacology,and,Serum,Pharmacochemistry,of,Traditional,Chinese,Medicine
Qun CHEN Ling HUANG Rui WANG Cong PANG
Abstract Serum pharmacochemistry of traditional Chinese medicine has become a more accurate and rapidly developing reasonable way to analyze the effective material basis of traditional Chinese medicine in recent years. Through this method， we can select very complex Chinese medicine components and clarify the effective substances consistent with the main functions， and then separate and purify effective ingredients in traditional Chinese medicine， so as to explain the material basis of the drug effect and prove the rationality and principle of action of Chinese medicine compounds. It can show the multi-component and multi-target characteristic of traditional Chinese medicine， and after analyzing the migrating components of serum， we can explore the direct effective substances that act on the patient"s body， so as to accelerate and accurately complete the in-depth study of the effective substances of Chinese medicine.
Key words Traditional Chinese Medicine Field; Serum pharmacology; Serum pharmacochemistry; Application overview; Chinese herbal compound
Serum pharmacology was first clearly proposed by the famous Japanese medical scientist Masakazu Tashiro at the first Chinese Medicine Conference in 1984. It refers to a new experimental method in which experimental animals are subjected to blood tests and serum separation after a certain period of time after oral administration of drugs and in vitro pharmacological testing is then completed through the drug-containing serum. Serum pharmacology has brought a new research basis for scientifically explaining the functions and principles of traditional Chinese medicine compounds[1]. In 1997， Chinese scholars represented by Wang Xijun introduced the definition and theoretical methods of serum pharmacology of traditional Chinese medicine into the field of medical research in China， and the further analysis of serum pharmacology of traditional Chinese medicine also began to be promoted and developed[2]. Compared with the inherent experimental method directly applying traditional Chinese medicine to the human body， serum pharmacology can better reflect the true response to traditional Chinese medicine in human metabolism， and it also brings new directions and focus to the pharmacological analysis of traditional Chinese medicine. Therefore， in the analysis process of traditional Chinese medicine， especially compound pharmacology， it has become more and more obvious that serum pharmacology of traditional Chinese medicine has played a good role in the heart and cerebral vessels， nervous system， respiratory system， immunity， digestion， reproduction， urination， bones， and antibacterial， anti-inflammatory， anti-tumor and anti-viral aspects， and also brings important methods to the pharmacological analysis of Chinese herbal compounds.
Research Status of Serum Pharmacology
Regarding the different analysis goals， we must first deal with the main problems in the preparation of "drug-containing serum"， including the selection of donor experimental animals， the medication plan， and the time of blood collection. In addition to the effects of serum endogenous components， the differences in drug absorption between animals of different quality and ages and changes in blood drug components and concentrations caused by different drug dosages and blood collection duration all will bring certain obstacles to the separation and judgment of active serum components. If these problems are ignored or not handled properly， the authenticity and reliability of the analyzed data will be affected easily， and the repeatability of the entire research will be significantly reduced.
Appropriate selection of experimental animals providing drug-containing serum
In order to further improve the safety and reliability of experimental results and reduce the biological， physical and chemical specificity of animal serum and human serum， it is necessary to select some animals with biological characteristics similar to humans to prepare the drug-containing serum， so as to create an environment most close to the human body[3]. Now the medical community mainly chooses rabbits and rats for experiments. For example， when analyzing the action sites of the anti-inflammatory activity of Smilaz china L.， healthy animals cannot explain the activity condition and activity metabolism of drugs in the blood under pathological conditions. The selection of healthy animals or simulated animals needs to be specifically defined according to the results of drug efficacy testing.
Blood collection and sample treatment
Because the components of traditional Chinese medicine are often very complicated， and the peak time of different medicine components is also different， there is actually no uniform requirement for the blood drawing time. The proper blood collection time needs to be controlled at the stage with maximum blood drug concentration， so as to avoid false negative test results due to incomplete absorption or metabolism of the effective substances. After exploring many pharmacokinetic parameters of traditional Chinese medicine， a correct and feasible medication plan is brought forward：
for example， medicating 2 times a day， 3 d continuously， and drawing the blood in time 1 h after the last medication. Generally speaking， the blood drawing time is mainly between 0.5 and 3 h after the last plicated， so the drug-containing serum eventually turns into drug metabolism serum with the increase of time easily， and it may also cause the peak value of some pharmaceutical ingredients to have passed or not reached. Generally speaking， the blood drawing time must be clarified according to the digestive characteristics of experimental animals and the absorption characteristics of traditional Chinese medicine[4]. Because there are many endogenous impurities in serum samples， the concentration of samples is very low， and the number of samples is limited， it usually needs to separate， purify or enrich samples before testing. At present， the most important treatment methods include organic solvent extraction， protein precipitation （protein precipitation methods such as heavy metal salts， organic solvents， organic acids， etc.）， hot water baths， solid phase extraction， and ultrafiltration. The goal of all these methods is to make the migrating components in the blood highly enriched， and the influencing components are eliminated as much as possible. By comparing different treatment methods， the most suitable serum treatment process can be finally determined.
Specific design of medication plan
The modern method is to increase the dose by 5-20 times on the basis of the original prescription and continuously apply the target ingredients for 5 to 7 half-lives， or take the "average steady-state concentration" of the important ingredients as a guide to clarify the medication time. It can also be calculated according to the formula of "drug dose = clinical constant × animal equivalent dose coefficient × medium dilution"， which should be 10 or 30 times the clinical daily average dose. However， this method is not suitable for complex prescriptions with complex medicinal flavors and larger doses[5]. According to the technical standards of new drug pharmacological analysis， when designing the dosage and medication， the drug-containing serum is developed as a freeze-dried powder to inject into experimental animals， which can not only increase the drug content in the blood of experimental animals， but also promote the preservation of serum， thereby achieving the required concentration in animal serum. The response surface method can be used to analyze the changes of drug concentration， blood collection time， and frequency of medication against chlorogenic acid and forsythin in Yinqiaotiangan-containing serum to improve the preparation technology of Yinqiaotiangan-containing serum. However， most of the current preparation and analysis of drug-containing serum are analyzed by pharmacodynamic parameters， seldom analyze chemical parameters， and ignore the interaction between various influencing factors[6]. Or with animal modelling， medication interval， blood drawing time， and blood components as observation factors， and the increase of liver injury cells， the change in the content of alanine aminotransferase and the level of schisandrin B in the drug-containing serum as observation indexes， an orthogonal test combining the pharmacological and chemical parameters for weighting can be carried out to analyze the proper preparation process of the drug-containing serum of Yinchenhaotang.
Practical Application of Serum Pharmacochemistry in Traditional Chinese Medicine
Practical application in the process of effective material basis of Chinese herbal compounds
The analysis of the effective material basis of the compound preparation Xiefei Pingchuanling by serum pharmacochemistry revealed that there were as many as 18 migrating components in the blood of experimental rats， most of which， 10 components could be directly digested and absorbed by the affected body， and the rest should be the products of prototype components through metabolism. During the serum pharmacochemistry analysis of Gushuling， it was found that 21 blood components were included， 11 of which were derived from the prototypes of the compound， 4 were newly formed substances， and the rest were metabolites. The medication plan of traditional Chinese medicine is mainly to clarify the dosage form， medication method， dosage， medication interval， medication time and treatment course， and drug combination[7]. In the past， the administration of traditional Chinese medicine generally were not set with clear medication duration， medication interval， as well as dosage and course of medication， were usually formulated by the doctor"s experience， while the design of a scientific medication plan must be completed by accurate measurement of the human blood concentration.
Practical application based on identification of effective substances of Chinese medicine
The analysis on the material basis of the efficacy of traditional Chinese medicine has become the focus of the modernization of traditional Chinese medicine. However， the components of traditional Chinese medicine are very complex and are in extremely complicated correlation， and the reaction of the medicine with different human bodies change and differ greatly. As a result， the modernization of Chinese medicine has encountered serious problems such as unclear medicinal substances. Although traditional Chinese medicine has many components， which can be absorbed in the human body， and the metabolism process is very complicated， only those effective components or metabolites that are actually digested and absorbed into the blood can finally exert the expected efficacy[8]. When studying the material basis of the medicines containing Dracocephalum moldavica L. sold in pharmacies for maintaining hypoxia/reoxygenation damage of cardiomyocytes according to the research methods of serum pharmocochemistry and pharmacology， it was observed that there were 4 kinds of components of D. moldavica absorbed into human serum， of which 75% belonged to the prototype components， and the remaining 25% were metabolic components. Therefore， it can be determined that the 4 components absorbed into the blood extracted from D. moldavica are the pharmaceutical substances that can prevent the cardiomyocytes from being damaged by hypoxia/reoxygenation.
Practical application in explaining the compound compatibility mechanism of traditional Chinese medicine
Because the components of Chinese herbal compounds are very complex， and most of them are taken orally， when the drugs are absorbed into the blood， the distribution processes and the actual effects of the main substances are different from the extracted auxiliary components and other components. These factors have also led to certain obstacles to the analysis of compatibility laws to some extent[9]. In recent years， many research methods applied in serum pharmacochemistry have usually played an effect and significance on the compound compatibility mechanism. By means of serum pharmacochemistry， the effects of different compatible components on blood migration were analyzed and observed for the Suanzaoren Decoction sold in pharmacies. It was found that there were 7 components absorbed into the blood of Suanzaoren Decoction， and such migrating components could be selectively absorbed and entered into the blood by the human body under combination conditions. The effective ingredients or component groups extracted from animal drugs， botanical drugs， and minerals have become the key method for the development of new drugs[10]. Understanding the small molecule substances and metabolites sourced from Chinese medicines according to the method of serum pharmacochemistry and detecting the actual pharmacological effects according to the method of serum pharmacology to grasp the effective ingredients and ingredient groups and then using the obtained effective ingredients or ingredient groups as basic raw materials to complete the research and development of new drugs has become a new way to promote the correct development of new drugs. For example， in the process of comparing the serum chemistry of rats intragastrically administrated with chemical extracts of jujube and jujube， 17 kinds of effective ingredients were found again.
Conclusions
In summary， the establishment of the research method of serum pharmacochemistry can be said to open up a new direction for the research of Chinese herbal compounds. It provides necessary technical support for analyzing the material basis of Chinese medicine efficacy and explaining the material basis of Chinese medicine action. The joint discussion of serum pharmacochemistry and serum pharmacology of traditional Chinese medicine can help explain the effective material basis and fundamental principles of Chinese herbal compounds. The fingerprints of traditional Chinese medicine are now a new type of analysis mode and research system of the material basis of traditional Chinese medicine， and if the establishment of fingerprints is integrated with serum pharmacochemistry， it will be able to clearly explain the material basis of traditional Chinese medicine. On the whole， serum pharmacology and serum pharmacochemistry of traditional Chinese medicine have strong development potential and application value， and with the further improvement of modern analytical technology and the common development of many disciplines， they will eventually become important tools and guarantee for the basic analysis of traditional Chinese medicine and thus better promote the scientific and sustainable development of modernization of Chinese traditional medicine.
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