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ObjectiveTo identify the prototypical components and metabolites absorbed into blood and cerebrospinal fluid of Schisandrae Chinensis Fructus（SCF） based on sequential metabolism combined with liquid chromatography-mass spectrometry. MethodBlood and cerebrospinal fluid samples of integrated metabolism， intestinal metabolism and hepatic metabolism were collected from male SD rats after gavage and in situ intestinal perfusion administration， and ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（UPLC Q-Exactive Orbitrap MS） was used to analyze and compare the differences in the spectra of SCF extract， blank plasma， administered plasma， blank cerebrospinal fluid and administered cerebrospinal fluid with ACQUITY UPLC BEH Shield RP18 column（2.1 mm×100 mm， 1.7 µm）， the mobile phase was acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution（0-7 min， 95%B； 7-12 min， 95%-35%B； 12-17 min， 35%-15%B； 17-20 min， 15%-12%B； 20-22 min， 12%-5%B； 22-23 min， 5%B； 23-25 min， 5%-95%B； 25-28 min， 95%B）. And heated electrospray ionization（HESI） was used with positive and negative ion modes， the scanning range was m/z 100-1 500. The prototypical constituents and their metabolites absorbed into blood and cerebrospinal fluid of SCF were identified according to the retention time， characteristic fragments， molecular formulae and the information of reference substances. ResultA total of 42 chemical components were identified in the extract of SCF， including lignans， flavonoids， amino acids， tannins， and others， of which lignans were the main ones. A total of 27 prototypical components and 14 metabolites were identified in plasma samples from different sites. A total of 15 prototypical components and 9 metabolites were identified in cerebrospinal fluid. The main metabolic reactions involved in the formation of metabolites were mainly demethylation， methylation， demethoxylation and hydroxylation. ConclusionThrough the systematic identification of the prototypical components and metabolites of SCF in rats， it provides data support for further better exploring the material basis of SCF in the treatment of central nervous system diseases.
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Deciphering the metabolites of multiple components in herbal medicine has far-reaching significance for revealing pharmacodynamic ingredients.However,most chemical components of herbal medicine are secondary metabolites with low content whose in vivo metabolites are close to trace amounts,making it difficult to achieve comprehensive detection and identification.In this paper,an efficient strategy was proposed:herb-derived metabolites were predicted according to the structural characteristics and metabolic reactions of chemical constituents in Corydalis Rhizoma and chemical structure screening tables for metabolites were conducted.The fragmentation patterns were summarized from represen-tative standards combining with specific cleavage behaviors to deduce structures of metabolites.Ion abundance plays an important role in compound identification,and high ion abundance can improve identification accuracy.The types of metabolites in different biological samples were very similar,but their ion abundance might be different.Therefore,for trace metabolites in biological samples,we used the following two methods to process:metabolites of high dose herbal extract were analyzed to char-acterize those of clinical dose herbal extracts in the same biological samples;cross-mapping of different biological samples was applied to identify trace metabolites based on the fact that a metabolite has different ion abundance in different biological samples.Compared with not using this strategy,44 more metabolites of clinical dose herbal extract were detected.This study improved the depth,breadth,and accuracy of current methods for herb-derived metabolites characterization.
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BACKGROUND: Although the mechanism of femoral head necrosis has a series of explanations such as glucocorticoids, ethanol, decompression sickness, sickle cell anemia, and genetic susceptibility, the specific pathogenesis is still unclear. OBJECTIVE: To highlight the genetics of non-traumatic femoral head necrosis by combining recent genetic studies, thus providing new treatments for the repair and reconstruction of femoral head. METHODS: A computer-based online retrieval of CNKI, WanFang, PubMed and Web of Science databases was performed to search the related articles published from January 2000 to April 2019. The keywords were “non-traumatic femoral head necrosis, susceptibility genes, pathogenesis” in Chinese and English, respectively. According to the inclusion and exclusion criteria, the irrelevant and repetitive articles were excluded, and finally 49 eligible articles were included for analysis. RESULTS AND CONCLUSION: Non-traumatic femoral head necrosis is an extremely complex disease whose pathogenesis is caused by a combination of factors rather than a single genetic gene. COL2A1 genetic mutation is the high susceptibility gene to non-traumatic femoral head necrosis. High-coagulation and low-fibrinolytic state-related loci in the blood, interleukin-related gene loci in immune system and lipid-related loci become more and more important in inducing non-traumatic femoral head necrosis. With the deep understanding of human genetic technology, the accuracy of detecting susceptible genes will be continuously improved, which is conducive to the prevention, diagnosis and precise individualized treatment of non-traumatic femoral head necrosis.
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The study was conducted to characterize the pharmacokinetics, distribution, metabolism and excretion of CHMFL-FLT3-122 after a single oral dose of 50 mg·kg-1 [14C] labeled CHMFL-FLT3-122 in rats. Isotope tracing techniques were used to analyze drug concentration and identify the distribution of drugs in tissues and metabolites in biological samples. The experiments were approved by the Animal Ethics Committee of XenoBiotic Laboratories-China, Inc. The absolute bioavailability in male and female rats were 45.83% and 50.92% respectively. The parent drug and its metabolites were extensively distributed in the stomach, intestine, liver and lung, and were eliminated completely in 48 h. The majority of radioactivity was excreted through the feces at 92.34% of the dose with a small fraction through urine at 3.99% of the dose. The parent drug was the most significant circulating component, representing 49.23% and 70.65% over the 0-48 h collection time interval in the plasma of male and female. Two major metabolites, M553 (sulfate conjugate) and M457 (N-dealkyl product), were identified in plasma. Metabolites of CHMFL-FLT3-122, including ten phase I and four phase II metabolites, were identified. The metabolic pathways of CHMFL-FLT3-122 were proposed as N-dealkylation, oxidation, amide hydrolysis, sulfate conjugation, and glucuronic conjugation.
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The mass spectrometry-based metabolomics method was used to systematically investigate the formation of celastrol metabolites,and the effect of celastrol on endogenous metabolites. The mice plasma,urine and feces samples were collected after oral administration of celastrol. Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry( UPLC-QTOF-MS) was applied to analyze the exogenous metabolites of celastrol and its altered endogenous metabolites. Mass defect filtering was adopted to screen for the exogenous metabolites of celastrol. Multivariate statistical analysis was used to identify the endogenous metabolites affected by celastrol. Celastrol and its eight metabolites were detected in urine and feces of mice,and 5 metabolites of them were reported for the first time. The hydroxylated metabolites were observed in the metabolism of both human liver microsomes and mouse liver microsomes. Further recombinant enzyme experiments revealed CYP3 A4 was the major metabolic enzyme involved in the formation of hydroxylated metabolites. Urinary metabolomics revealed that celastrol can affect the excretion of intestinal bacteria-related endogenous metabolites,including hippuric acid,phenylacetylglycine,5-hydroxyindoleacetic acid,urocanic acid,cinnamoylglycine,phenylproplonylglycine and xanthurenic acid. These results are helpful to elucidate the metabolism and disposition of celastrol in vivo,and its mechanism of action.
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Animals , Humans , Mice , Chromatography, High Pressure Liquid , Mass Spectrometry , Metabolomics , Microsomes, Liver , Metabolism , Triterpenes , Metabolism , PharmacokineticsABSTRACT
Saponins are important components in traditional Chinese medicine (TCM) with significant biological activities, which could be divided into triterpenoid saponins and steroidal saponins according to structures of the aglycone skeletons. This article reviews the in vivo metabolic pathways of some typical natural saponins such as ginsenosides, licorice saponins, saikosaponins, timosaponins and diosgenin glycosides. Saponins often show poor absorbance after oral administration. The in vivo metabolism of saponins generally contain two steps. These compounds usually undergo hydrolysis in stomach and gut. Then they are absorbed into blood and metabolized in liver. The secondary glycosides and the aglycones produced in gastrointestinal tract often show higher bioavailability and better bioactivity, while downstream metabolites in liver are mainly produced by phase I metabolism. Clarification of the in vivo metabolism of bioactive saponins is helpful for the understanding of the effective ingredients in TCM, as well as the discovery of new drugs from natural products.
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Steaming method is a traditional processing method for Gastrodiae Rhizoma(GR). The current studies on the steaming method's mechanism of GR are mainly focused on facilitating softening slice, destroying the β-glycosidic bond enzymes to reduce the decomposition of gastrodia glycosides (killing enzyme and protecting glycosides). The researches on the processing mechanism are still incomplete, while revealing and analyzing the active components in the body's metabolic process are important channels and new models to clarify the mechanism of traditional medicine processing. In order to provides a reference for the in-depth study of the processing mechanism of GR, we have reviewed the relevant literature at home and abroad in recent years and briefly summarized the processing, composition analysis and in vivo metabolism of GR in this study.
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Drug metabolism research plays an essential role in drug discovery and development. Great efforts have been made domestically to be line with the international standardized research on drug metabolism. In this article, we will review new-generation of tyrosine kinase inhibitors (TKIs), these TKIs include icotinib, apatinib, famitinib, flumatinb, allitinib, fruquintinib, and selatinib, among which icotinib and apatinib have been approved by China food and drug administration (CFDA) to reach the market, while others are in clinical trials. For these TKIs, the structural modified sites are active metabolic centers and CYP3A4 is identified as the primary metabolic enzyme. Considering the active intermediates, the crown ether ring of icotinib is oxidated to open to form an aldehyde; the indolylidene ring of famitinib is oxidated followed by rearrangement to form a quinone-imine; the α, β-unsaturated carbonyl group of allitinib is oxidated to form an epoxide, these intermediates are capable of covalently binding biomolecules and generating toxicity. In addition, human 14C radioactive trials of most of these TKIs have not been conducted, and the data of drug-drug interactions in clinic are also absent, which indicate our deficiency compared to the international regular approaches in metabolic research.
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Gene is the base of in vivo metabolism and effectiveness for traditional Chinese medicines (TCM), and the gene expression, regulation and modification are used as the research directions to perform the TCM multi-component, multi-link and multi-target in vivo metabolism studies, which will improve the research on TCM metabolic proecess, effect target and molecular mechanism. Humans are superorganisms with 1% genes inherited from parents and 99% genes from various parts of the human body, mainly coming from the microorganisms in intestinal flora. These indicate that genetically inherited human genome and "second genome" could affect the TCM in vivo metabolism from inheritance and "environmental" aspects respectively. In the present paper, typical case study was used to discuss related TCM in vivo metabolic genomics research, mainly including TCM genomics research and gut metagenomics research, as well as the personalized medicine evoked from the individual difference of above genomics (metagenomics).
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Gynostemma pentaphyllum belonged to the Cucurbitaceae family.It was also called theQi-Ye-Dan,licorice stem,Gong-Luo Guo-Di,and etc.It contained saponin,flavonoids,polysaccharides,terpenoids and other chemical compositions.Its pharmacological effects included cholesterol-lowering activity,antitumor activity,hypoglycemic activity,anti-aging and boost immunity.This paper reviewed the research progress on chemical constituents,pharmacological effects and in vivometabolism of gynostemma pentaphyllum,in order to provide a theoretical basis for its further research and development.
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Traditional Chinese medicine (TCM) contains a big array of chemical constituents. These constituents un-dergo various metabolic reactions to produce complex in v iv o metabolites. Identification and distribution of these metabolites are important to reveal the effective constituents from a complex formulation. Recently, developments had been made to elucidate the complex metabolic process. In this review, we summarized the methods and strategies developed for TCM metabolism. Application of these metabolic results has also been discussed.
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Traditional Chinese medicines(TCM) are taken orally in most cases, and their chemical constituents generally have low blood concentrations and poor oral bioavailabilities. The absorbed chemical constituents of TCM, especially the in vivo biotransformed products might play an important role in explaining the effectiveness, and even the toxicities and side effects of TCM. Up to now, most of the studies on the in vivo metabolites of TCM constituents are still limited to structural identification, and only a few researches on the bioactivities and toxicities of the metabolites have been carried out since they are not easy to obtain. Therefore, the preparation of in vivo metabolites is necessary for deeply investigating how and why TCM show the effectiveness or toxicity. Based on the studies of our group on the metabolism of TCM bioactive compounds in recent years, the preparation methods for in vivo metabolites are summarized, which might be helpful for the study of metabolism of TCM.
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OBJECTIVE: To investigate the metabolic profile of senecionine in rats. METHODS: Liquid chromatography-tandem mass spectrometry (LC-MSn) mass spectrometry was used for the analysis of senecionine and its metabolites in rats bile, urine, and feces after a single oral dose of senecionine. RESULTS: In total 38 metabolites were identified, including oxidation products, hydroxylation products, hydrolysis products, sulfation products, glucuronidation products, and GSH-conjugations. And metabolites were found to be more abundant in bile and urine than those in feces. CONCLUSION: Senecionine undergoes extensive metabolism in rats.
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Traditional Chinese Materia Medica (TCMM) has a long history for its application in treating diseases, and has been proved in clinic for its efficacies. In the most cases, these medicines are taken orally, and the oral bioavailabilities of their chemical constituents are generally poor, and one of the most important causes is that the chemical constituents are biotransformed in gastrointestinal tract or in liver due to the in vivo chemical and biological circumstances. Since the pharmacological effects are considered to be derived from the absorbed chemical substances, we believe some biotransformed products might play an important role for the effectiveness of TCMM. Although the study on chemical constituents of TCMM has made significant achievements in the past three decades, the study on in vivo metabolism of TCMM constituents has still been in slow progress. In order to promote the research progress in this field, this paper will give some suggestions and ideas based on the current research situation, and some examples are presented to reveal the role of in vivo metabolism of chemical constituents in clarifying effective substance of TCMM.
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Gender-related differences in drug pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. Major molecular factors involved in drug disposition include drug-metabolising enzymes and drug transporters. Oxidative drug metabolism by cytochrome P450 (CYP) enzymes is a major pathway for drug elimination. CYP3A4,the major human drug-metabolizing CYP enzymes,has repeatedly been suggested higher metabolic activity in women than that in men,which sex-dependent secretory patterns of growth hormone that may be responsible for.