Studies On Pharmacokinetics And Interactions Of Xiao-ai-ping Injection

Xiao-Ai-Ping injection, the preparation from the aqueous extract of Marsdeniatenacissima, is shown to be clinically effective in treatment of gastric carcinoma, livercancer and lung cancer when combined with chemotherapy.As we know, the constituentsof Traditional Chinese medicine(TCM) are very complicated, especially when it comes tocombined drug usage, it’s likely to cause drug-drug interaction. So finding out themechanism of interaction between TCM and other chemotherapy drug tends to be essential,which can not only give support to clinical therapy, but also promote the extension of TCMall over the world.The content includes three main part.1. Study on the quality control of Xiao-ai-ping injection.A simple and reliable high performance liquid chromatography method coupled withan evaporative light scattering detecter (HPLC-ELSD) was developed for simultaneousdetermination of seven bioactive constituents (17β-Tenacigenin B, Tenacigenin B,Tenacigenin A, Tenacigenoside A, Marsdenoside I, Tenacissoside F and Tenacissoside A)in Xiao-ai-ping injection by optimizing the extraction, separation and analytical conditionsof HPLC-ELSD. The chromatographic separations were obtained by an Agilent EclipseXDB-C18reserved-phase column (250mm×4.6mm i.d.,5μm) using gradient elution withacetonitrile and water, at a flow rate of0.8mL/min, an operating temperature of35oC. Theconstituents were confirmed by (+/-) electrospray ionization UPLC-Q-TOF. The newmethod was validated and was successfully applied to simultaneous determination ofcomponents in11batches of Xiao-ai-ping injection. The results indicated that thismulti-component determination method in combination with chromatographic fingerprintanalysis is suitable for quantitative analysis and quality control ofXiao-ai-ping injection.2. Development and validation of a LC-MS/MS method the simultaneous determination ofthe main compents in Xiao-ai-ping injection in rat plasma.A sensitive and specific liquid chromatography tandem mass spectrometry(LC-MS/MS) method was developed and validated for for simultanenous determination ofthree isomeric pregnane genins (17β-Tenacigenin B、Tenacigenin B and Tenacigenin A)and their glycosides (Tenacigenoside A、Marsdenoside I and Tenacissoside F) in the ratplasma. A simple liquid-liquid extraction technique was used after the addition of dexamethasone acetate as internal standard (IS). Detection was performed by multiplereaction monitoring (MRM) mode using electrospray ionization in the negative ion mode.The validated method was successfully applied to study the pharmacokinetics profileof the major compounds of Xiao-Ai-Ping injection after intravenous administration.threeisomeric pregnane genins eliminated more rapidly compared with their correspondingglycosides. The t1/2of Marsdenoside I was less than that of tenacigenoside A andtenacissoside F. It revealed that Marsdenoside I was cleared more rapidly from rat plasmathan tenacigenoside A and tenacissoside F did. The results indicated that specificconfiguration might affect the elimination of polyoxypregnane glycosides, while thisrequired further investigation to confirm.3. The effects of Xiao-ai-ping injection and its main compents on CYP450enzymesactivity.In order to evaluate the effect of Xiao-ai-ping injection and the main compents onCYP450enzymes, the metabolites of the specific substrate of CYP450enzymes weredetermined by LC-MS/MS. The extract of Xiao-ai-ping injecton and the C21steroidshaddifferent degrees of inhibition on the activities of CYP3A4, CYP2C9and CYP2C19invivo, while rat experiment showed that Xiao-ai-ping injecton could inhibit the metabolismof midazolam which was a substrate of CYP3A4. The results implied tha additionalattention should be paid when Xiao-ai-ping injection were administered concomitantlywith other clinical drugs.