靛玉红体内外代谢研究
摘要
靛玉红是中药青黛的抗肿瘤有效成分。该化合物对于慢性粒细胞白血病具有明显的抑制作用。研究发现靛玉红对人体广泛存在的细胞周期依赖性蛋白激酶(CDK)、Src激酶相关的肿瘤细胞生长有抑制作用。靛玉红及其衍生物可能成为针对有CDK、Src激酶参与的肿瘤的新一代抗肿瘤药物。
最近的研究发现靛玉红与丹参酮IIA作为辅助成分可增强APL细胞中四硫化四砷诱导的泛素化和PML - RARα的降解,加强髓样分化调节因子的再程序化和延长G1/G0阻滞期。丹参酮IIA与靛玉红通过增加负责运输硫化砷的水甘油通道蛋白9的含量,促使进入白血病细胞的硫化砷明显增多。
随着靛玉红被逐渐开发利用,对靛玉红的研究以及认识也需进一步深入,有必要对其体内过程进行研究。这对正确评价动物实验数据并外推至人体,指导临床合理用药有重要意义。本研究通过靛玉红的体内外代谢研究来探讨体内外代谢相关性,从而为靛玉红与其他中西药物合用时的安全性与合理性的研究提供部分依据。
第一部分体外研究
拟采用肝微粒体体外孵育实验,研究靛玉红在大鼠肝微粒体内的代谢情况,为理解该药代谢的机制、预测药物相互作用和药物代谢多态性提供依据。采用钙沉淀法制备大鼠肝微粒体,建立了肝微粒体体外代谢研究模型,以靛玉红为底物研究了该药在大鼠肝微粒体中的代谢行为,浓度为100ng/mL的靛玉红在大鼠肝微粒体中孵化3h内,检测到靛玉红的水解、氧化和双氧化代谢物。
建立LC-MS/MS测定肝微粒体孵育液中靛玉红浓度的方法。肝微粒体孵育液样品处理采用液-液提取,提取物经液相色谱-电喷雾串联质谱测定,5分钟内完成靛玉红的检测,工作曲线线形范围1-100ng/mL,日内、日间精密度分别小于3.6%、13.4%,平均回收率在94.0%和104.4%之间,检测限为0.5ng/mL。本方法灵敏度高,特异性好,可以用于肝微粒体孵育液样品的检测。
第二部分体内研究
探讨靛玉红在大鼠体内的代谢行为。选择健康雄性大鼠,灌胃给予靛玉红200mg/kg,连续收集4.5、8.5、12、24、36、48小时时间段的尿液和粪便及4、8、12、24小时时间段的胆汁,经液-液提取后用LC/MS-MS进行分析。检测到尿液、粪便和胆汁中存在13种代谢产物:还原、甲基化、水解、氧化、双氧化、双硫酸化、葡萄糖醛酸化、谷胱甘肽-2H、氧化+谷胱甘肽-2H、氧化+磺化、葡萄糖醛酸化+双氧化、双氧化+谷胱甘肽-2H、双氧化+双葡萄糖醛酸化。
Indirubin is the major anti-carcinoma active ingredient of Indigo naturalis of Traditional Chinese drug. It has significant inhibitory effect on chronic myeloid leukemia. The inhibitory effect of indirubin and its derivatives on cell growth was found in some human tumor cell lines relating with cyclin dependent kinase(CDK) or Src kinase which widely exists in human bodies. Indirubin and its derivatives may become the new anti-tumor medicine for therapy of cancers that have CDK, Src kinase.
Indirubin and tanshinone IIA serve as adjuvant components to intensify tetraarsenic tetrasulfate-induced ubiquitination and degradation of PML-RARα, strengthen reprogramming of myeloid differentiation regulators and enhance G1/G0 arrest in APL cells. Indirubin and tanshinone IIA increase cellular uptake of arsenic by inducing up-regulation of Aquaglyceroporin 9 (AQP9) which is a transmembrane protein governing arsenic uptake and cellular sensitivity of arsenic.
In recent years, indirubin has attracted increasing interest due to its various beneficial biological activities to human health, which made it necessary to further study the metabolism of indirubin to elucidate its biological effects. It is important for rational evaluation of animal data as well as extrapolation to humans, and for guiding clinical use. Our study focused on the in vivo and in vitro metabolism of indirubin to explain the in vivo and in vitro correlation of indirubin metabolism, and evaluate the security and rationality of co-administration of indirubin with western medicine and traditional Chinese medicine.
1. Study On The Metabolism Of Indirubin In Rat Liver Microsomes
Rat liver microsomes were used for the research of metabolism of indirubin in vitro. It is helpful in the further understanding of indirubin metabolic mechanism, the prediction of pharmacokinetic drug-drug interactions and interpatient variability in drug exposure. Liver microsomes of male S.D. rats were prepared using calcium ion precipitation method. The in vitro metabolism of indirubin was studied by incubation with rat liver microsomes. Three phase I metabolites of indirubin were detected in rat liver microsomal incubates with 100ng/mL of indirubin and 3h of incubation. These metabolites were identified as hydrolysis, oxidization and di-oxidization metabolites of indirubin.
This article describes a sensitive and selective method for the determination of indirubin in microsomal incubates. A liquid–liquid extraction procedure was used. The extracts were analyzed by liquid chromatography–electrospray ionization tandem mass spectrometry using ketoconazole as an internal standard. The excellent sensitivity and selectivity of the liquid chromatography–tandem mass spectrometry method allowed quantitation and identification of indirubin at low levels with a run time of 5.0 minutes. A linear calibration range spanned 1-100 ng/mL. The relative standard deviations for the intra-day and inter-day precision were less than 3.6% and 13.4%, respectively. The average recoveries varied between 94.0% and 104.4%. The limit of detection was 0.5 ng/mL. Because of its simplicity and accuracy, the established method is suitable for the application in the determination of indirubin in microsomal incubates.
2. Study on the Metabolisms of Indirubin in Rats
To investigate the metabolism of indirubin in rats. Urine, fence samples at 4.5、8.5、12、24、36、48h and bile samples at 4、8、12、24h were collected after a single dose of 200 mg/kg indirubin was administered to rats. The urine, fence and bile samples were extracted by liquid-liquid Extraction and then analyzed with LC/MS-MS. 13 metabolites were identified in rats’urine, fence and bile, that is, Reduction, Methylation, Hydrolysis, Oxidation, Di-Oxidation, Di-Sulfation, Glucuronidation, Glutathione conjugation - 2H, Oxidation + Glutathione - 2H, Oxidation+Sulfonation, Glucuronidation + Di-Oxidation, Di-Oxidation + Glutathione - 2H, Di-Oxidation + Di-Glucuronidation.
最近的研究发现靛玉红与丹参酮IIA作为辅助成分可增强APL细胞中四硫化四砷诱导的泛素化和PML - RARα的降解,加强髓样分化调节因子的再程序化和延长G1/G0阻滞期。丹参酮IIA与靛玉红通过增加负责运输硫化砷的水甘油通道蛋白9的含量,促使进入白血病细胞的硫化砷明显增多。
随着靛玉红被逐渐开发利用,对靛玉红的研究以及认识也需进一步深入,有必要对其体内过程进行研究。这对正确评价动物实验数据并外推至人体,指导临床合理用药有重要意义。本研究通过靛玉红的体内外代谢研究来探讨体内外代谢相关性,从而为靛玉红与其他中西药物合用时的安全性与合理性的研究提供部分依据。
第一部分体外研究
拟采用肝微粒体体外孵育实验,研究靛玉红在大鼠肝微粒体内的代谢情况,为理解该药代谢的机制、预测药物相互作用和药物代谢多态性提供依据。采用钙沉淀法制备大鼠肝微粒体,建立了肝微粒体体外代谢研究模型,以靛玉红为底物研究了该药在大鼠肝微粒体中的代谢行为,浓度为100ng/mL的靛玉红在大鼠肝微粒体中孵化3h内,检测到靛玉红的水解、氧化和双氧化代谢物。
建立LC-MS/MS测定肝微粒体孵育液中靛玉红浓度的方法。肝微粒体孵育液样品处理采用液-液提取,提取物经液相色谱-电喷雾串联质谱测定,5分钟内完成靛玉红的检测,工作曲线线形范围1-100ng/mL,日内、日间精密度分别小于3.6%、13.4%,平均回收率在94.0%和104.4%之间,检测限为0.5ng/mL。本方法灵敏度高,特异性好,可以用于肝微粒体孵育液样品的检测。
第二部分体内研究
探讨靛玉红在大鼠体内的代谢行为。选择健康雄性大鼠,灌胃给予靛玉红200mg/kg,连续收集4.5、8.5、12、24、36、48小时时间段的尿液和粪便及4、8、12、24小时时间段的胆汁,经液-液提取后用LC/MS-MS进行分析。检测到尿液、粪便和胆汁中存在13种代谢产物:还原、甲基化、水解、氧化、双氧化、双硫酸化、葡萄糖醛酸化、谷胱甘肽-2H、氧化+谷胱甘肽-2H、氧化+磺化、葡萄糖醛酸化+双氧化、双氧化+谷胱甘肽-2H、双氧化+双葡萄糖醛酸化。
Indirubin is the major anti-carcinoma active ingredient of Indigo naturalis of Traditional Chinese drug. It has significant inhibitory effect on chronic myeloid leukemia. The inhibitory effect of indirubin and its derivatives on cell growth was found in some human tumor cell lines relating with cyclin dependent kinase(CDK) or Src kinase which widely exists in human bodies. Indirubin and its derivatives may become the new anti-tumor medicine for therapy of cancers that have CDK, Src kinase.
Indirubin and tanshinone IIA serve as adjuvant components to intensify tetraarsenic tetrasulfate-induced ubiquitination and degradation of PML-RARα, strengthen reprogramming of myeloid differentiation regulators and enhance G1/G0 arrest in APL cells. Indirubin and tanshinone IIA increase cellular uptake of arsenic by inducing up-regulation of Aquaglyceroporin 9 (AQP9) which is a transmembrane protein governing arsenic uptake and cellular sensitivity of arsenic.
In recent years, indirubin has attracted increasing interest due to its various beneficial biological activities to human health, which made it necessary to further study the metabolism of indirubin to elucidate its biological effects. It is important for rational evaluation of animal data as well as extrapolation to humans, and for guiding clinical use. Our study focused on the in vivo and in vitro metabolism of indirubin to explain the in vivo and in vitro correlation of indirubin metabolism, and evaluate the security and rationality of co-administration of indirubin with western medicine and traditional Chinese medicine.
1. Study On The Metabolism Of Indirubin In Rat Liver Microsomes
Rat liver microsomes were used for the research of metabolism of indirubin in vitro. It is helpful in the further understanding of indirubin metabolic mechanism, the prediction of pharmacokinetic drug-drug interactions and interpatient variability in drug exposure. Liver microsomes of male S.D. rats were prepared using calcium ion precipitation method. The in vitro metabolism of indirubin was studied by incubation with rat liver microsomes. Three phase I metabolites of indirubin were detected in rat liver microsomal incubates with 100ng/mL of indirubin and 3h of incubation. These metabolites were identified as hydrolysis, oxidization and di-oxidization metabolites of indirubin.
This article describes a sensitive and selective method for the determination of indirubin in microsomal incubates. A liquid–liquid extraction procedure was used. The extracts were analyzed by liquid chromatography–electrospray ionization tandem mass spectrometry using ketoconazole as an internal standard. The excellent sensitivity and selectivity of the liquid chromatography–tandem mass spectrometry method allowed quantitation and identification of indirubin at low levels with a run time of 5.0 minutes. A linear calibration range spanned 1-100 ng/mL. The relative standard deviations for the intra-day and inter-day precision were less than 3.6% and 13.4%, respectively. The average recoveries varied between 94.0% and 104.4%. The limit of detection was 0.5 ng/mL. Because of its simplicity and accuracy, the established method is suitable for the application in the determination of indirubin in microsomal incubates.
2. Study on the Metabolisms of Indirubin in Rats
To investigate the metabolism of indirubin in rats. Urine, fence samples at 4.5、8.5、12、24、36、48h and bile samples at 4、8、12、24h were collected after a single dose of 200 mg/kg indirubin was administered to rats. The urine, fence and bile samples were extracted by liquid-liquid Extraction and then analyzed with LC/MS-MS. 13 metabolites were identified in rats’urine, fence and bile, that is, Reduction, Methylation, Hydrolysis, Oxidation, Di-Oxidation, Di-Sulfation, Glucuronidation, Glutathione conjugation - 2H, Oxidation + Glutathione - 2H, Oxidation+Sulfonation, Glucuronidation + Di-Oxidation, Di-Oxidation + Glutathione - 2H, Di-Oxidation + Di-Glucuronidation.
引文
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1.梁文权,方晓玲,高申,生物药剂学与药物动力学. 2003.
2. Bernard Ttsta and Han van de Waterbeemd, ADME-Tox approaches. 2006.
3. A. Tolonen, M. Turpeinen, and O. Pelkonen, Liquid chromatography-mass spectrometry in in vitro drug metabolite screening. Drug Discov Today, 2009. 14(3-4): p. 120-33.
4. Christopher L. Shaffer Chandra Prakash, Angus Nedderman,, Analytical strategies for identifying drug metabolites. Mass Spectrometry Reviews, 2007. 26(3): p. 340-369.
5. Walter A. Korfmacher, Using Mass Spectrometry For Drug Metabolism Studies 2005.
6. Daniel B. Kassel, Applications of high-throughput ADME in drug discovery. Current Opinion in Chemical Biology, 2004. 8(3): p. 339-345.
7. J. M. Castro-Perez, Current and future trends in the application of HPLC-MS to metabolite-identification studies. Drug Discov Today, 2007. 12(5-6): p. 249-56.
8. M. Holcapek, L. Kolarova, and M. Nobilis, High-performance liquid chromatography-tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites. Anal Bioanal Chem, 2008. 391(1): p. 59-78.
9. K. Levsen, et al., Structure elucidation of phase II metabolites by tandem mass spectrometry: an overview. J Chromatogr A, 2005. 1067(1-2): p. 55-72.
10. Li Ma Ming Yao, W. Griffith Humphreys, Mingshe Zhu, Rapid screening and characterization of drug metabolites using a multiple ion monitoring-dependent MS/MS acquisition method on a hybrid triple quadrupole-linear ion trap mass spectrometer. Journal of Mass Spectrometry, 2008. 43(10): p. 1364-1375.
11. Emmanuel Varesio, et. al. Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. Journal of Mass Spectrometry, 2004. 39(8): p. 845-855.
12. J. C. Yves Le Blanc James W. Hager, Product ion scanning using a Q-q-Q linear ion trap (Q TRAP) mass spectrometer. Rapid Communications in Mass Spectrometry, 2003. 17(10): p. 1056-1064.
13. James W. Hager J. C. Yves Le Blanc, A. M. Patricia Ilisiu, Christie Hunter, Feng Zhong, Ivan Chu,, Unique scanning capabilities of a new hybrid linear ion trap mass spectrometer (Q TRAP) used for high sensitivity proteomics applications. Proteomics, 2003. 3(6): p. 859-869.
14.美国应用生物系统中国公司技术服务部, Analyst软件应用培训教程Q TRAP部分.
15. Identification of Phase I and Phase II Metabolites of Buspirone on the Q TRAP?.
16. J. F. Mora, et al., Electrochemical processes in electrospray ionization mass spectrometry. J Mass Spectrom, 2000. 35(8): p. 939-52.
17. S. Nguyen and J. B. Fenn, Gas-phase ions of solute species from charged droplets of solutions. Proc Natl Acad Sci U S A, 2007. 104(4): p. 1111-7.
18.美国应用生物系统中国公司技术服务部,美国应用生物系统公司性能超群、型号齐全的高科技质谱家族系列及其应用简介.
19. Keith Waddel, API 3000/2000 Operator Course Analyst Software. 2002.
20.美国应用生物系统公司, Analyst on-line help.
21.美国应用生物系统公司, Metabolite ID on-line help.
22. Advanced Chemistry Development, ACD/ChemSketch—Reference Manual Comprehensive Interface Description. 2007.
23. Advanced Chemistry Development, ACD/ChemSketch Tutorial—Drawing Chemical Structures and Graphical Images. 2007.
24. Advanced Chemistry Development, ACD/Dictionary User's Guide—Looking up Chemical Structures. 2007.
25. Advanced Chemistry Development, ACD/3D Viewer User's Guide—Viewing 3D Structures and Calculating their Structural Parameters. 2007.
26. Advanced Chemistry Development, ACD/IntelliXtract User’s Guide—Intelligent Component Extraction, and Identification of Protonated/Deprotonated Molecular Weights and Differences Between Samples 2008.
27. Advanced Chemistry Development, ACD/MS Manager & MS Processor Tutorial—Processing and Organizing Experimental Mass Spectrometry Data. 2007.
28. Advanced Chemistry Development, ACD/MS Manager &Processor Reference Manual—Processing and Organizing Experimental Mass Spectrometry Data. 2007.
29. Graham McGibbon Margaret Antler, and Mark Bayliss, How to Optimize the ACD/IntelliXtract Input Parameters.
30. Advanced Chemistry Development, ACD/SpecDB and ACD/SpecDB Enterprise Tutorial—Managing Spectral or Chromatographic Databases. 2007.
31. Advanced Chemistry Development, ACD/SpecDB and ACD/SpecDB Enterprise Reference Manual—Managing Spectral or Chromatographic Databases. 2007.
32.美国应用生物系统公司, LightSight User's Guide.
33. H. Licea-Perez, S. Wang, and C. Bowen, Development of a sensitive and selective LC-MS/MS method for the determination of alpha-fluoro-beta-alanine, 5-fluorouracil and capecitabine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci, 2009.
34. D. Zhang, et al., A sensitive method for the determination of entecavir at picogram per milliliter level in human plasma by solid phase extraction and high-pH LC-MS/MS. J Pharm Biomed Anal, 2009.
35. E. M. Suenaga, et al., Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS. Application to a bioequivalence study. J Sep Sci, 2009. 32(4): p. 637-43.
36. N. A. Gomes, et al., Validated LC-MS/MS method for determination of Alverine and one of its hydroxy metabolites in human plasma along with its application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci, 2009. 877(3): p. 197-206.
37. B. N. Patel, et al., An accurate, rapid and sensitive determination of tramadol and its active metabolite O-desmethyltramadol in human plasma by LC-MS/MS. J Pharm Biomed Anal, 2009. 49(2): p. 354-66.
38. J. Wen, et al., Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers. J Pharm Biomed Anal, 2009. 49(2): p. 347-53.
39. Emmanuel Varesio Lekha Sleno, Gerard Hopfgartner,, Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactivemetabolite in covalent binding. Rapid Communications in Mass Spectrometry, 2007. 21(24): p. 4149-4157.
40. Christophe Husser, et. al. Rapid screening and characterization of drug metabolites using a new quadrupole-linear ion trap mass spectrometer. Journal of Mass Spectrometry, 2003. 38(2): p. 138-150.
41. W. Z. Shou, et al., A novel approach to perform metabolite screening during the quantitative LC-MS/MS analyses of in vitro metabolic stability samples using a hybrid triple-quadrupole linear ion trap mass spectrometer. J Mass Spectrom, 2005. 40(10): p. 1347-56.
42. A. C. Li, M. A. Gohdes, and W. Z. Shou, 'N-in-one' strategy for metabolite identification using a liquid chromatography/hybrid triple quadrupole linear ion trap instrument using multiple dependent product ion scans triggered with full mass scan. Rapid Commun Mass Spectrom, 2007. 21(8): p. 1421-30.
43. Dennis Alton Austin C. Li, Matthew S. Bryant, Wilson Z. Shou,, Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument. Rapid Communications in Mass Spectrometry, 2005. 19(14): p. 1943-1950.
44. T. Mauriala, et al., A strategy for identification of drug metabolites from dried blood spots using triple-quadrupole/linear ion trap hybrid mass spectrometry. Rapid Commun Mass Spectrom, 2005. 19(14): p. 1984-92.
45.美国应用生物系统公司, Improving the Metabolite Identification Process with Efficiency and Speed: LightSightTM Software for Metabolite Identification.
46.美国应用生物系统公司, Identification of Metabolites using a Predictive MRM-IDA Method Created by the Automated Method Creation Tool in LightSightTM Software.
47.美国应用生物系统公司, LightSightTM Software and Q TRAP System Technology: Making it Easier to Obtain Full Metabolite Coverage.
48. Walter A. Korfmacher, USING MASS SPECTROMETRY FOR DRUG METABOLISM STUDIES 2005.
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25. Scott M. Peterman, et al., Application of a Linear Ion Trap/Orbitrap Mass Spectrometerin Metabolite Characterization Studies: Examination of the Human Liver Microsomal Metabolism of the Non-Tricyclic Anti-Depressant Nefazodone Using Data-Dependent Accurate Mass Measurements. Journal of the American Society for Mass Spectrometry, 2006. 17(3): p. 363-375.
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35. E. F. Brandon, et al., Structure elucidation of aplidine metabolites formed in vitro by human liver microsomes using triple quadrupole mass spectrometry. J Mass Spectrom, 2005. 40(6): p. 821-31.
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37. D. Zhang, et al., A sensitive method for the determination of entecavir at picogram per milliliter level in human plasma by solid phase extraction and high-pH LC-MS/MS. J Pharm Biomed Anal, 2009.
38. J. Wen, et al., Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers. J Pharm Biomed Anal, 2009. 49(2): p. 347-53.
39. E. M. Suenaga, et al., Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS. Application to a bioequivalence study. J Sep Sci, 2009. 32(4): p. 637-43.
40. B. N. Patel, et al., An accurate, rapid and sensitive determination of tramadol and its active metabolite O-desmethyltramadol in human plasma by LC-MS/MS. J Pharm Biomed Anal, 2009. 49(2): p. 354-66.
41. H. Licea-Perez, S. Wang, and C. Bowen, Development of a sensitive and selective LC-MS/MS method for the determination of alpha-fluoro-beta-alanine, 5-fluorouracil and capecitabine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci, 2009.
42. N. A. Gomes, et al., Validated LC-MS/MS method for determination of Alverine and one of its hydroxy metabolites in human plasma along with its application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci, 2009. 877(3): p. 197-206.
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45. Advanced Chemistry Development, ACD/MS Manager & MS Processor Tutorial—Processing and Organizing Experimental Mass Spectrometry Data. 2007.
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1.梁文权,方晓玲,高申,生物药剂学与药物动力学. 2003.
2. Bernard Ttsta and Han van de Waterbeemd, ADME-Tox approaches. 2006.
3. A. Tolonen, M. Turpeinen, and O. Pelkonen, Liquid chromatography-mass spectrometry in in vitro drug metabolite screening. Drug Discov Today, 2009. 14(3-4): p. 120-33.
4. Christopher L. Shaffer Chandra Prakash, Angus Nedderman,, Analytical strategies for identifying drug metabolites. Mass Spectrometry Reviews, 2007. 26(3): p. 340-369.
5. Walter A. Korfmacher, Using Mass Spectrometry For Drug Metabolism Studies 2005.
6. Daniel B. Kassel, Applications of high-throughput ADME in drug discovery. Current Opinion in Chemical Biology, 2004. 8(3): p. 339-345.
7. J. M. Castro-Perez, Current and future trends in the application of HPLC-MS to metabolite-identification studies. Drug Discov Today, 2007. 12(5-6): p. 249-56.
8. M. Holcapek, L. Kolarova, and M. Nobilis, High-performance liquid chromatography-tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites. Anal Bioanal Chem, 2008. 391(1): p. 59-78.
9. K. Levsen, et al., Structure elucidation of phase II metabolites by tandem mass spectrometry: an overview. J Chromatogr A, 2005. 1067(1-2): p. 55-72.
10. Li Ma Ming Yao, W. Griffith Humphreys, Mingshe Zhu, Rapid screening and characterization of drug metabolites using a multiple ion monitoring-dependent MS/MS acquisition method on a hybrid triple quadrupole-linear ion trap mass spectrometer. Journal of Mass Spectrometry, 2008. 43(10): p. 1364-1375.
11. Emmanuel Varesio, et. al. Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. Journal of Mass Spectrometry, 2004. 39(8): p. 845-855.
12. J. C. Yves Le Blanc James W. Hager, Product ion scanning using a Q-q-Q linear ion trap (Q TRAP) mass spectrometer. Rapid Communications in Mass Spectrometry, 2003. 17(10): p. 1056-1064.
13. James W. Hager J. C. Yves Le Blanc, A. M. Patricia Ilisiu, Christie Hunter, Feng Zhong, Ivan Chu,, Unique scanning capabilities of a new hybrid linear ion trap mass spectrometer (Q TRAP) used for high sensitivity proteomics applications. Proteomics, 2003. 3(6): p. 859-869.
14.美国应用生物系统中国公司技术服务部, Analyst软件应用培训教程Q TRAP部分.
15. Identification of Phase I and Phase II Metabolites of Buspirone on the Q TRAP?.
16. J. F. Mora, et al., Electrochemical processes in electrospray ionization mass spectrometry. J Mass Spectrom, 2000. 35(8): p. 939-52.
17. S. Nguyen and J. B. Fenn, Gas-phase ions of solute species from charged droplets of solutions. Proc Natl Acad Sci U S A, 2007. 104(4): p. 1111-7.
18.美国应用生物系统中国公司技术服务部,美国应用生物系统公司性能超群、型号齐全的高科技质谱家族系列及其应用简介.
19. Keith Waddel, API 3000/2000 Operator Course Analyst Software. 2002.
20.美国应用生物系统公司, Analyst on-line help.
21.美国应用生物系统公司, Metabolite ID on-line help.
22. Advanced Chemistry Development, ACD/ChemSketch—Reference Manual Comprehensive Interface Description. 2007.
23. Advanced Chemistry Development, ACD/ChemSketch Tutorial—Drawing Chemical Structures and Graphical Images. 2007.
24. Advanced Chemistry Development, ACD/Dictionary User's Guide—Looking up Chemical Structures. 2007.
25. Advanced Chemistry Development, ACD/3D Viewer User's Guide—Viewing 3D Structures and Calculating their Structural Parameters. 2007.
26. Advanced Chemistry Development, ACD/IntelliXtract User’s Guide—Intelligent Component Extraction, and Identification of Protonated/Deprotonated Molecular Weights and Differences Between Samples 2008.
27. Advanced Chemistry Development, ACD/MS Manager & MS Processor Tutorial—Processing and Organizing Experimental Mass Spectrometry Data. 2007.
28. Advanced Chemistry Development, ACD/MS Manager &Processor Reference Manual—Processing and Organizing Experimental Mass Spectrometry Data. 2007.
29. Graham McGibbon Margaret Antler, and Mark Bayliss, How to Optimize the ACD/IntelliXtract Input Parameters.
30. Advanced Chemistry Development, ACD/SpecDB and ACD/SpecDB Enterprise Tutorial—Managing Spectral or Chromatographic Databases. 2007.
31. Advanced Chemistry Development, ACD/SpecDB and ACD/SpecDB Enterprise Reference Manual—Managing Spectral or Chromatographic Databases. 2007.
32.美国应用生物系统公司, LightSight User's Guide.
33. H. Licea-Perez, S. Wang, and C. Bowen, Development of a sensitive and selective LC-MS/MS method for the determination of alpha-fluoro-beta-alanine, 5-fluorouracil and capecitabine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci, 2009.
34. D. Zhang, et al., A sensitive method for the determination of entecavir at picogram per milliliter level in human plasma by solid phase extraction and high-pH LC-MS/MS. J Pharm Biomed Anal, 2009.
35. E. M. Suenaga, et al., Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS. Application to a bioequivalence study. J Sep Sci, 2009. 32(4): p. 637-43.
36. N. A. Gomes, et al., Validated LC-MS/MS method for determination of Alverine and one of its hydroxy metabolites in human plasma along with its application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci, 2009. 877(3): p. 197-206.
37. B. N. Patel, et al., An accurate, rapid and sensitive determination of tramadol and its active metabolite O-desmethyltramadol in human plasma by LC-MS/MS. J Pharm Biomed Anal, 2009. 49(2): p. 354-66.
38. J. Wen, et al., Simultaneous determination of rupatadine and its metabolite desloratadine in human plasma by a sensitive LC-MS/MS method: application to the pharmacokinetic study in healthy Chinese volunteers. J Pharm Biomed Anal, 2009. 49(2): p. 347-53.
39. Emmanuel Varesio Lekha Sleno, Gerard Hopfgartner,, Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactivemetabolite in covalent binding. Rapid Communications in Mass Spectrometry, 2007. 21(24): p. 4149-4157.
40. Christophe Husser, et. al. Rapid screening and characterization of drug metabolites using a new quadrupole-linear ion trap mass spectrometer. Journal of Mass Spectrometry, 2003. 38(2): p. 138-150.
41. W. Z. Shou, et al., A novel approach to perform metabolite screening during the quantitative LC-MS/MS analyses of in vitro metabolic stability samples using a hybrid triple-quadrupole linear ion trap mass spectrometer. J Mass Spectrom, 2005. 40(10): p. 1347-56.
42. A. C. Li, M. A. Gohdes, and W. Z. Shou, 'N-in-one' strategy for metabolite identification using a liquid chromatography/hybrid triple quadrupole linear ion trap instrument using multiple dependent product ion scans triggered with full mass scan. Rapid Commun Mass Spectrom, 2007. 21(8): p. 1421-30.
43. Dennis Alton Austin C. Li, Matthew S. Bryant, Wilson Z. Shou,, Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument. Rapid Communications in Mass Spectrometry, 2005. 19(14): p. 1943-1950.
44. T. Mauriala, et al., A strategy for identification of drug metabolites from dried blood spots using triple-quadrupole/linear ion trap hybrid mass spectrometry. Rapid Commun Mass Spectrom, 2005. 19(14): p. 1984-92.
45.美国应用生物系统公司, Improving the Metabolite Identification Process with Efficiency and Speed: LightSightTM Software for Metabolite Identification.
46.美国应用生物系统公司, Identification of Metabolites using a Predictive MRM-IDA Method Created by the Automated Method Creation Tool in LightSightTM Software.
47.美国应用生物系统公司, LightSightTM Software and Q TRAP System Technology: Making it Easier to Obtain Full Metabolite Coverage.
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