| Traditional Chinese Medicine(TCM) with its long history was mainly used inthe form of Complex Prescription in clinic. But the research on pharmacodynamicfoundation of Complex Prescription of Traditional Chinese Medicine(CPTCM) waslagging. It was significant to carry out researches on metabolism of CPTCM, whichwas helpful to reveal the pharmacodynamic foundation, to analyze kinesis process invivo and to seek compatibility regularity of CPTCM.Ma-huang-tang decoction, a famous complex prescription in TCM, had beenused for thousands of years in China. It was composed of Chinese herbs like HerbaEphedrae(Ma-huang), Cortex Cinnamomi(Gui-zhi), Semen ArmeniacaeAmarum(Xing-ren) and Radix Glycyrrhizae(Gan-cao), which was recorded in anancient medical book named 'Shang Han Lun' by Zhang Zhong-Jing, a famousdoctor in ancient China. The main effect of this decoction were relieving fever,sweating and relieving cough. In clinical applications, it had been mainly used forthe treatment for upper respiratory tract infection, bronchitis, bronchial asthma, andetc. And the therapeutic effect was proved remarkably. According topharmacological researches of Ma-huang-tang decoction and Ma-huang, we couldsee that the role of sweationg and relieving cough of the decoction was closely related to Ma-huang, which was primary in Ma-huang-tang decoction. The primaryactive components in Ma-huang were large amounts of Ephedrine(E) and smallamounts of Pseudoephedrine(PE), and smaller amounts of closely related alkaloids,namely Norephedrine(NME), Norpseudoephedrine(NMP) andMethylephedrine(ME). In this study, we analyzed the five ephedra alkaloids inMa-huang-tang decoction, and plasma and urine from huaman after oraladministration of Ma-huang-tang decoction. And the regularity about metabolismand excretion of ephedra alkaloids in vivo was approached, which was helpful toreveal the pharmacodynamic foundation of Ma-huang-tang decoction.Objective:To research the metabolism and excretion of the five ephedra alkaloids inhuman body after oral administration of Ma-huang-tang decoction, and to illuminatethe pharmacodynamic foundation of Ma-huang-tang decoction.Methods:1. Looked up articles about pharmacology, toxicology, biotransformation,metabolism and excretion of Ma-huang-tang decoction and ephedra alkaloids by theway of computer retrieval and manual retrieval, and making use of many kinds ofdatabases, such as CNKI, PubMed, SienceDirect, SpringerLINK, CA, Toxnet andect.2. Combined with present study and clinical medication, the preparation methodof Ma-huang-tang decoction and Ma-huang decoction was set, on the basis ofpreparation of Ma-huang-tang decoction recorded in an ancient medical book named'Shang Han Lun'. So the Ma-huang-tang decoction and Ma-huang decoction wereprepared. The same volume of Ma-huang-tang decoction was taken at a draught byevery participant. Plasma at 2h post-administration was collected. And urine samples were collected at 2h, 4h, 6h, 8h, 10h, 14h, 22h, 24h after administration. The fivekinds of Ephedra alkaloids in these samples were measured by GasChromatography-Mass Spectrometry (GC-MS).3. With the help of SPSS 13.0 and by the method of Independent-Samples T Test,the concentration and content of each ephedra alkaloids in Ma-huang-tang decoctionwas compared respectively with that in Ma-huang decoction; By the method ofOne-Sample T Test, cumulative excreted amount of each ephedra alkaloids at 24hpost-administration was compared respectively with the amount taken orally, and thecumulative excreted percentage for each alkaloid was compared respectively with l;By the method of Reapted Measures, the excretion amounts of NMP, NME, E, PEand ME at different time were compared with each other.4. The excretion information of each ephedra alkaloids in urine was describedwith average cumulative excreted amount and average cumulative excretedpercentage.Results:1. By making use of several retrieval tools and Chinese-English databases,hundreds of literatures were read. It's known that carrying out the metabolism ofCPTCM was helpful to reveal pharmacodynamic foundation. Sweating and relievingcough as the main role of this decoction, was correlated with ephedra alkaloids.There were less reports on biotransformation and metabolism of Ma-huang relatedcomplex preparations, while more researches were reported when ephedra alkaloidwas taken in the form of sigle.2. NMP, NME, E, PE and ME were determined and separated in 24min byGC-MS. These methods were proved accurate, with good specificity andreproducibility, and high sensitivity.3. The concentration of NMP, NME, E, PE and ME in Ma-huang-tang decoction was respectively 13.27μg·mL-1, 9.83μg·mL-1, 295.31μg·mL-1,79.26μg·mL-1, 18.66μg·mL-1, and the content was respectively 4.38mg, 3.24mg,97.45mg, 26.15mg, 6.16mg. While The concentration of NMP, NME, E, PE and MEin Ma-huang decoction was respectively 16.67μg·mL-1, 11.96μg·mL-1,321.52μg·mL-1, 87.99μg·mL-1, 19.55μg·mL-1, and the content was respectively6.42mg, 4.61mg, 123.79mg, 33.88mg, 7.53mg. The concentration and content ofNMP, NME, E, PE and ME in Ma-huang-tang decoction was significantly lowerthan that in Ma-huang decoction (P＜0.05).4. E, PE and ME existed in plasma at 2h post-administration. They wereseparated and determined by GC-MS. The concentration was respectively 186.57ng·mL-1, 32.45 ng·mL-1, 22.62 ng·mL-1. But NMP and NME were not detected.5. Time as a factor significantly influnenced the excretion of ephedra alkaloids(P＜0.001). E and PE excreted most quickly during 4-8h post-administration, whileNME, NMP and ME excreted most quickly during 4-6h post-administration;Acorrding to the average cumulative excreted content-time curves of ephedraalkaloids in urine, we could see that E excreted most quickly, while ME excretedmost slowly at each time.6. The average cumulative excreted content of NMP, NME, E, PE and ME inurine at 24h post-administration of Ma-huang-tang decoction was respectively5.20mg, 9.46mg, 68.39mg, 23.73mg, 2.35mg, while average cumulative excretedpercentage was respectively 118.85％, 291.97％, 70.18％, 90.75％, 38.10％. NMPand NME were notable with high cumulative excreted content and cumulativeexcreted percentage. According to statistic results, cumulative excreted content ofNMP and NME was significantly (P＜0.05) higher than the taken orally content,while the cumulative excreted percentage was significantly (P＜0.05) higher than 1.Conclusion: 1. NMP, NME, E, PE and ME were present in Ma-huang-tang decoction. Andthe content and concentration of the five ephedra alkaloids in Ma-huang-tangdecoction was respectively less than that in Ma-huang decoction. This indicated thatwhen Ma-huang was prescribed together with Gui-zhi, Xing-ren and Gan-cao, theamount of the five ephedra alkaloids in the decoction declined. In bothMa-huang-tang decoction and Ma-huang decoction, there were large amounts of E,followed by PE, and smaller amounts of closely related alkaloids, namely NME,NMP and ME.2. E, PE and ME had been absorbed into blood circulation at 2h postadministration. Then a part of E, PE and ME was metabolized as unchanged parentcompounds, while reciprocal transformation also existed. By the way ofsummarizing of the experiment results and related reports, the metabolic behaviorsin vivo of ephedra alkaloids after oral administration Ma-huang-tang decoction weresupposed as follows: E was mainly metabolized as unchanged parent component,while a small part of E was metabolized as NME; PE was mainly metabolized asoriginal component, while a few of PE was metabolized as NMP; A part of ME wasmetabolized as unchanged, while a part of it was metabolized as E, and then NME.NME and NMP was mainly metabolized as unchanged. The chemical constituentsin plasma were proved to be the pharmacodynamie foundation of CPTCM byplasma-pharmacology. Therefore, E, PE and ME may be the pharmacodynamiccompounds of Ma-huang-tang decoction.3. 24h later after administraon of Ma-huang-tang decoction, a large amount ofNMP, NME, E and PE was excreted in urine in the form of original compounds inassistance of kidney, while a small amount for ME. The excretion velocity ofephedra alkaloids at 4-6h post-adimistration of Ma-huang-tang decoction was asfollows: E＞PE＞NME＞NMP＞ME. These results support the role of fast sweating and lasting preventiong cough of Ma-huang-tang decoction.4. In this study, new methods without derivatization of simultaneousdetermination of the five Ephedra alkaloids in Ma-huang-tang decoction andMa-huang decoction, plasma and urine had been established by our team. Thesemethods were proved to be accurate, convenient and in good reproducibility, whichwere helpful for clinical detection and studies on pharmacokinetic of Ephedraalkaloids. |
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