体外代谢用于中药活性成分筛选的研究
|
摘要
中药现代化面临的主要问题是物质结构的鉴定、有效成分筛选以及中药药理的建立。现代药物筛选手段并不适用于多成分、多靶点、组合药效的中药活性成分筛选,因此针对中药的筛选新方法不断出现。本文对近年来的中药筛选方法进行了较全面的综述,这些方法多注重相互作用而忽略体内过程。针对中药特点和目前新药(西药)的发展思路,本论文建立了动物肝匀浆中药体外代谢方法,并以此为平台结合体外药理试验,采用HPLC-MS 等分析手段将中药成分代谢指纹谱与活性试验有机结合起来用于中药活性成分筛选。
建立了SD 大鼠肝匀浆体外代谢方法,通过考察非那西丁在肝匀浆中的代谢,初步验证了本实验所采用的全肝匀浆体外代谢方法的可靠性。在此基础上,以单味中药黄柏等为样品,采用HPLC 辅以MALDI-TOF-MS 对代谢前后的指纹谱差异与相似性进行比较,进而验证本实验采用的代谢平台用于中药代谢与筛选的可行性。
以体外代谢为平台,对单味中药丹参、大黄及其主要活性成分进行体外代谢,结合抑菌、血凝、抗肿瘤体外试验测定提取物及其代谢物、主要成分的活性。从代谢的角度解释了丹参、大黄的抗菌、血凝、抗肿瘤活性在代谢前后变化的原因,并筛选出其中活性成分。
以体外代谢平台结合体外抗肿瘤实验在中药川芎的活性成分中筛选出一种具有抗肿瘤活性的的化合物——阿魏酸松柏酯,同时鉴定了它的代谢产物。阿魏酸松柏酯显示出较好的抑制Hela 细胞的活性,而其代谢产物则没有活性,从而解释了粗提物在代谢前后抗肿瘤活性变化的原因。
Illuminating of constitutes, screening of bioactive components andestablishing of pharmacology in traditional Chinese medicines (TCMs) are thekey subjects for modernization of TCMs. High-throughput screening techniqueused in development of synthetic drugs does not meet the pharmacology of TCMson account of their multi-component, multi-target and combined effect in therapy.Whereas the facts, many new strategies have been developed for screeningconstitutes of TCMs in the past decades. In this thesis, the present state of the artof screening strategies for bioactive compounds in TCMs are summarized, it isindicated that the interaction between drugs and targets but changes in vivo weremostly focused.
The metabolizing fingerprinting analysis of TCMs has been developed forpharmacological screening by rat liver homogenate in vitro. The method ofmetabolism in vitro has been estabolished by SD rat liver homogenate. Themetabolism of phenacetinum was investigated for availability. The diversity andcomparability about extracts of Cortex Phellodendri etc. was analyzed before andafter metabolism in vitro by means of chromatographic and MALDI-TOF-MSfingerprints.
By means of the metabolism methods in vitro, antimicrobial activities,agglutination and antineoplastic activity were determined from the extracts,metabolites and components of Radix Salviac miltiorrhizae and Radix et RhizomaRhei by pharmacological assays in vitro. The changes of activities were caused
from the metabolism of some components in TCMs, and the bioactivecomponents with metabolism activity were discovered simultaneously. An antineoplastic compound, coniferyl ferulate, was screened and identifiedfrom the extract of Rhizoma Chuanxiong by metabolism methods in vitro. Itsmetabolite was also identified as ferulic acid ethyl ester,and antineoplastic activityof this metabolite was not observed anymore. The proposed metabolism pathwayof coniferyl ferulate was illustrated in vitro.
建立了SD 大鼠肝匀浆体外代谢方法,通过考察非那西丁在肝匀浆中的代谢,初步验证了本实验所采用的全肝匀浆体外代谢方法的可靠性。在此基础上,以单味中药黄柏等为样品,采用HPLC 辅以MALDI-TOF-MS 对代谢前后的指纹谱差异与相似性进行比较,进而验证本实验采用的代谢平台用于中药代谢与筛选的可行性。
以体外代谢为平台,对单味中药丹参、大黄及其主要活性成分进行体外代谢,结合抑菌、血凝、抗肿瘤体外试验测定提取物及其代谢物、主要成分的活性。从代谢的角度解释了丹参、大黄的抗菌、血凝、抗肿瘤活性在代谢前后变化的原因,并筛选出其中活性成分。
以体外代谢平台结合体外抗肿瘤实验在中药川芎的活性成分中筛选出一种具有抗肿瘤活性的的化合物——阿魏酸松柏酯,同时鉴定了它的代谢产物。阿魏酸松柏酯显示出较好的抑制Hela 细胞的活性,而其代谢产物则没有活性,从而解释了粗提物在代谢前后抗肿瘤活性变化的原因。
Illuminating of constitutes, screening of bioactive components andestablishing of pharmacology in traditional Chinese medicines (TCMs) are thekey subjects for modernization of TCMs. High-throughput screening techniqueused in development of synthetic drugs does not meet the pharmacology of TCMson account of their multi-component, multi-target and combined effect in therapy.Whereas the facts, many new strategies have been developed for screeningconstitutes of TCMs in the past decades. In this thesis, the present state of the artof screening strategies for bioactive compounds in TCMs are summarized, it isindicated that the interaction between drugs and targets but changes in vivo weremostly focused.
The metabolizing fingerprinting analysis of TCMs has been developed forpharmacological screening by rat liver homogenate in vitro. The method ofmetabolism in vitro has been estabolished by SD rat liver homogenate. Themetabolism of phenacetinum was investigated for availability. The diversity andcomparability about extracts of Cortex Phellodendri etc. was analyzed before andafter metabolism in vitro by means of chromatographic and MALDI-TOF-MSfingerprints.
By means of the metabolism methods in vitro, antimicrobial activities,agglutination and antineoplastic activity were determined from the extracts,metabolites and components of Radix Salviac miltiorrhizae and Radix et RhizomaRhei by pharmacological assays in vitro. The changes of activities were caused
from the metabolism of some components in TCMs, and the bioactivecomponents with metabolism activity were discovered simultaneously. An antineoplastic compound, coniferyl ferulate, was screened and identifiedfrom the extract of Rhizoma Chuanxiong by metabolism methods in vitro. Itsmetabolite was also identified as ferulic acid ethyl ester,and antineoplastic activityof this metabolite was not observed anymore. The proposed metabolism pathwayof coniferyl ferulate was illustrated in vitro.
引文
1. Chen K, Xu H. The integration of traditional Chinese medicine and Western medicine. Eur. Rev. 2003, 11(2), 225-235
2. 姚新生. 借鉴国际传统药物发展经验推动中药现代化进程. 世界科 学技术-中药现代化. 2002, 4(3):6-12
3. 姚新生,胡柯. 中药复方的现代化研究. 化学进展. 1999,2:192-196
4 Yan X, Zhou J, Xie G.. Traditional Chinese Medicines. Burlington, VT: Ashgate Publishing Co., 2000.
5 Nigel Wiseman. Traditional Chinese Medicine: A Brief Outline. J. Chem. Inf. Comput. Sci. 2002, 42: 445-455
6 汤少梁,王高玲. 点击中药出口. 中国药业. 2002,11(11):8-10
7 王序,李荣芷,韩桂秋. 研究常用中药活性成分途径的探讨. 北京医 学院学报. 1982,14(4):372-375
8 王序,韩桂秋,李荣芷,潘竞先,陈雅研,何云庆,涂馥,王邠, Huang L,Lee C,Sandrino M,Chang M,Shen T. 现代生物分析法 对常用中药的筛选研究. 北京医科大学学报. 1986,18(1):31-36
9 江黎明,李志明,韩宝铬. 神经生长因子受体活性中草药及其成分 的筛选. 中草药. 1994,25(2): 79-81, 105
10 田代真—.“血清药理学”と“血清药化学”——汉方の药理学ガぃ 始まった药物血中浓度测定の新しぃ世界. TDM 研究. 1988,5: 54
11 陈耀祖. 中药复方化学研究策略诹议. 化学进展. 1999,11(2): 188-192
12 Lin H J, Lu Y H A. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol. Rev. 1997, 49(4): 403-449
13 杜冠华,胡娟娟,夏丽娟,黄家学,张均田. 药物筛选的发展与现 状. 药学学报. 1998,33(11):876-879
14 张志琪,张延妮,田振军. 药物筛选模型和技术及其在中药活性成 分研究中的应用. 中国中药杂志. 2003,28(10): 907-910
15 Itokawa H, Takeya K, Mihara K, Mori N, Hamanaka T, Sonobe T, Iitaka Y. Studies on the antitumor cyclic hexapeptides obtained from Rubiae radix. Chem. Pharm. Bull. 1983, 31(4): 1424-1427
16 Enslein K. An overview of structure-activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicol. Ind. Health. 1988, 4: 479-498
17 Johnston M V, Trescher W H, Ishida A, Nakajima W. Novel treatments after experimental brain injury. Semin Neonatol. 2000, 5: 75-86
18 吴镭. 药学科学前沿与发展方向. 北京: 中国医药科技出版社, 2000. 89,118.
19 胡娟娟, 杜冠华. 药物筛选模型研究进展. 基础医学与临床. 2001, 21(4): 302-305
20 鲁春娥,武士华. 转基因动物与药物筛选. 国外医学药学分册. 1997, 24(6): 330-334
21 叶文红. 敲除技术及转基因动物模型在遗传病研究中的应用. 国外 医学遗传学分册. 2002,25(5): 252-255
22 李发荣, 吴臻, 杨建雄. 现代生物技术在中药活性组分筛选中的应 用. 中国中药杂志. 2004,24(11): 1099-1101
23 Mickisch G H, Merlino G T, Galski H, et al. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identificat ion of agents that reverse drug resistance. Proc. Natl.
Acad. Sci. U S A. 1991, 88(1): 547-551
24 Porter G M, Armstrong L, Nielsen L L. Strategy for developing transgenic assays for screening antineoplastic drugs that affect tubulin polymerization. Lab. Anim. Sci. 1995, 45(2):145-150
25 胡愉, 张建民, 王红, 何维. 一种中药方剂对PDAPP 转基因小鼠行 为能力的影响. 中国神经免疫学和神经病学杂志. 2004, 11(1): 17-21
26 朱梅菊, 张红, 郭振球. 新制抗癌方对AFB1染毒的HBV转基因小鼠 肝癌前病变组织PCNA 等表达的影响. 中成药. 2004, 26(8): 682-684
27 徐敏,姜丽丽,梁文权,鲁沁渊. α-细辛醚透皮吸收促进剂的筛选. 中 国临床药学杂志. 2000,9(6): 369-370
28 苏连杰, 马文军,马友辉,张应成,吴波. 鸡胚法筛选具有血管生成 抑制作用中药的实验研究. 中医药信息. 2001,18(3): 65
29 司春峰,魏睦新. 中药促结肠动力作用的筛选研究. 中国中西医结合 消化杂志. 2003,11(6): 346-348
30 张素清,施雪筠. 几种中药保存离体心脏的筛选比较研究. 北京中医 药大学学报. 2003,26(2):39-41
31 Cox B, Denyer J C, Binnie A, Donnelly M C, Evans B, Green D V S, Lewis J A, Mander T H, Merritt A T, Valler M J, Watson S P. Application of high-throughput screening techniques to drug discovery. Prog. Med. Chem. 2000, 37: 83-133
32 张英华,金亚宏,严述常. 几种中药及复方抗肿瘤作用(体外)的实验 研究. 中药药理与临床. 1992,8(4): 7-9
33 张慧珠,杨林,任雷鸣,刘淑梅. 中药活性成分逆转肿瘤细胞多药 耐药作用的体外筛选. 华北煤炭医学院学报. 2003,5(3): 265-267
34 张艳军. 增强原代培养鼠胚脊髓运动神经元活力的中药筛选. 天津 中医学院学报. 2004,23(2): 75-77
35 钱慧林,钟良玉. 热毒清药液抗SARS 病毒细胞模型的实验研究. 中 国中医药科技. 2004,11(4): 214-215
36 Ho T Y, Wu S L, Lai I L, Cheng K S, Kao S T, Hsiang C Y. An in vitro system combined with an in-house quantitation assay for screening hepatitis C virus inhibitors. Antivir. Res. 2003, 58: 199-208
37 Shibata Y, Takahashi H, Ishii Y. A convenient in vitro screening method for predicting in vivo drug metabolic clearance using isolated hepatocytes suspended in serum. Drug Metab. Dispos. 2000, 28(12): 1518-1523
38 任德成,胡娟娟,杜冠华. 内皮细胞损伤筛选模型. 药学学报. 2000, 35(增刊): 44-47
39 Wodnicka M, Guarino R D, Hemperly J J, Timmins M R, Stitt D, Pitner J B. Novel fluorescent technology platform for high throughput cytotoxicity and pro-liferation assays. J. Biomol. Screen. 2000, 5(3): 141-152
40 陈永红,杜冠华. 筛选抗脑缺血药物的神经细胞模型. 药学学报. 2000,35(增刊): 21-24
41 Rowan S J, Sanders J K. Enzyme models: design and selection. Curr. Opin. Chem. Biol. 1997, 1: 483-490
42 Hodder P S, Ruzicka J. A flow injection renewable surface technique for cell-based drug discovery functional assays. Anal. Chem. 1999, 71(6): 1160-1166
43 黄家学,胡娟娟,杜冠华. 5-HT 受体结合物的高通量筛选. 药学学 报. 2000,35(增刊): 53-56
44 尚念勇,胡娟娟,杜冠华. 腺苷A1 受体结合物的高通量筛选. 药学 学报. 2000,35(增刊): 47-49
45 Venkataraman S, Martin S M, Schafer F Q, Buettner G R. Detailed methods for the quantification of nitric oxide in aqueous solutions using either an oxygen monitor or EPR. Free Radical. Bio. Med. 2000, 29(6): 580-585
46. Rees S A. Bioanalytical strategies to support a discovery research programme. J. Pharm. Biomed. Anal. 1996, 14: 1185-1190
47. Gillmor S A, Cohen F E. New strategies for pharmaceutical design. Receptor. 1993, 3(3): 155-163
48.孙秋,杨慧敏,褚红标,李铭刚,文孟良. 筛选新抗生素的方法. 云 南农业科技. 2003,4: 43-45
49. Black J. Drugs from emasculated hormones: the principle of syntopic antagonism. Science. 1989, 245(4917): 486-93
50. Kuntz I D. Structure-based strategies for drug design and discovery. Science. 1992, 257: 1078
51. 付青姐,刘叔文,吴曙光. 药物靶点的选择和验证. 生命科学研究. 2001,5(3 Suppl.): 206-209
52. 陈泽乃. 受体技术与新药开发. 中国药学杂志. 1994,29(6): 362-365
53. Alan D. Drug screening-beyond the bottleneck. Nat. Biotechnol. 1999, 17: 859-863
54. 王序,韩桂秋,李荣芷,潘竞先,陈雅研,何云庆,涂馥,王邠. 现 代生物分析法对常用中药的筛选研究. 中药药理与临床. 1985,10-11
55. 高虹,欧阳克清,郑旭煦,许治良,胡应和,蔡绍皙. 毒蕈胆碱M1 受体激动剂的高通量筛选模型. 中国药理学通报. 2003, 19(7):
776-779
56. 郑旭煦,欧阳克清,高虹,许治良,胡应和,蔡绍皙. 神经介素NMU2R 受体激动剂的高通量筛选模型研究. 中国药学杂志. 2004,39(3): 185-188
57. Yamada H, Oya I, Nagai T, Matsumoto T, Kiyohara H, Omura S. Screening of a-glucosidase II inhibitor from Chinese herbs and its application on the quality control of mulberry bark. Shoyakugaku Zasshi. 1993, 47(1): 47-55
58. Tang W, Sun X, Fang J S, Zhang M, Sucher N J. Flavonoids from Radix Scutellariae as potential stroke therapeutic agents by targeting the second postsynaptic density 95(PSD-95)/disc large/zonula occludens-1(PDZ) domain of PSD-95. Phytomedicine 2004, 11(6): 277-284
59. 唐赟,陈凯先,嵇汝运. 离子通道与药物设计. 药学进展. 1995,19(4): 197-205
60. Numann R, Negulescu P A. High-throughput Screening strategies for cardiac ion channels. Trends Cardiovas. Med. 2001, 11(2): 54-59
61. Xu J, Chen Y, Li M. High-throughput technologies for studying potassium channels-progresses and challenges. Rev. Res. Focus. 2004, 3(1): 32-38
62. 张奕华,彭司勋,华维一. 新药研究开发的进展与展望. 中国药科 大学学报. 1999,30(2): 153-158
63. 马全顺,尹世金,陈素,张凡,刘向明. 血竭总黄酮对小鼠三叉神 经节细胞河豚毒素敏感型钠通道电流的抑制作用. 中南民族大学学 报(自然科学版). 2004,23(3): 5-8
64. Neher E, Sadmann B. The patch clamp technique. J. Sci. Am. 1992, 266(3): 44-52
65.张礼和. 以核酸为作用靶的药物研究. 成都:成都科学出版社,1997. 146
66. Burke W. Genomics as a probe for disease biology. N. Engl. J. Med. 2003, 349(10): 969-974
67. 马云鹏. 480 种中草药提取物在体外对癌细胞DNA 作用模式的初步 研究. 中药通报. 1987,12(2): 56
68.邓沱,宁志强,周玉祥,程京. 生物芯片技术在药物研究与开发中 的应用. 中国新药杂志. 2002,11(1): 23-31
69. Heller R A, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J, Woolley DE, Davis RW. Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc. Natl. Acad. Sci. USA. 1997, 94(6): 2150-2155
70. Jellis C L, Cradick T J, Rennert P, Salinas P, Boyd J, Amirault T, Gray G S. Defining critical residues in the epitope for HIV-neutralizing monoclonal antibody using phage display and peptide array technologies. Gene. 1993,137(1): 63-68
71. Pietu G, Alibert O, Guichard V, Lamy B, Bois F, Leroy E, MariageSamson R, Houlgatte R, Soularue P, Auffray C. Novel gene transcripts preferentially expressed in human muscles revealed by quantitative hybridization of a high density cDNA array. Genome Res.1996, 6: 492-503
72 徐伟文,李文全. 高通量药物靶位基因筛选的策略与方法. 中国药学 杂志. 2002,37(4): 241-244
73. 胡岳山,李杰芬,谭宇蕙. 基因芯片技术在中药研究中的应用. 深圳 中西医结合杂志. 2004,14(1): 56-59
74. 托娅,苏秀兰,路桂荣,辛学东,王文礼,柯杨,包文宇. 基因芯 片在抗肿瘤血管生成中草药相关基因筛选中的研究. 第二军医大学 学报. 2002,23 (3): 273-275
75. 周联,王培训,赖小平,周华. 基因芯片在中药复方研究中的应用. 中 药新药与临床药理. 2002, 13(6): 383-384
76 Watanabe C M H, Wolffram S, Ader P, Rimbach G, Packer L, Maguire JJ, Schultz PG, Gohil K. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci. USA. 2001,98 (12): 6577-6580
77. Li X K, Motwani M, Tong W, Bornmann W, Schwartz G K. Huanglian, a Chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol. Pharmacol. 2000, 58 (6): 1287-1293
78. Hopfinger A J, Duca J S. Extraction of pharmacophore information from high2throughput screens. Curr. Opin. Biotechnol. 2000, 11(1): 97-103
79. Chaiken I M. Analytical affinity chromatography in studies of molecular recognition in biology. J Chromatogr. 1986, 376: 11-32
80. Kaliszan R. Quantitative Structure-Chromatographic Retentionships. NewYork: Wiley, 1987
81. Haginaka J, Seyama C, Murashima T. Retentive and enantioselective properties of ovomucoid-bonded silica columns-Influence of protein purity and isolation method. J. Chromatogr. A. 1995, 704(2): 279-287
82 Domenici E, Bertucci C, Salvadori P, Wainer I W. Use of a human serum albumin-based HPLC CSP for the investigation of protein-binding- detection of the allosteric interaction between Warfarin and Benzodiazepine binding-sites. J. Pharm. Sci. 1991, 80(2): 164-166
83. Wainer I W, Noctor T A G, Domenici E, Jadaud P. Chiral recognition on biopolyner-based HPLC CSPs -a case for multiple interaction sites. ACS Sym. Series. 1991, 471: 141-154
84 周维书,刘泽培等编著,药物相互作用──原理和生化基础,北京: 科学出版社,1990
85. Wang H, Zou H, Zhang Y. Quantitative study of competitive binding of drugs to protein by microdialysis/high performance liquid chromatography. Anal.Chem. 1998, 70: 373-377
86. Huang X, Kong L, Li X, Chen X, Guo M, Zou H. Strategy for Analysis and Screening of Bioactive Compounds in Traditional Chinese Medicines. J. Chromatogr. B. 2005, 812(1-2): 71-84
87. Wang H, Kong L, Zou H, Ni J, Zhang Y. Screening and analysis of biologically active compounds in Angelica sinensis by molecular biochromatography. Chromatographia. 1999, 50(7/8): 439-445
88. Wang H, Zou H, Ni J, Kong L, Gao S, Guo B. Fractionation and analysis of Artemisia capillaries Thunb. by affinity chromatography with human serum albumin as stationary phase. J. Chromatogr. A. 2000, 870: 501-510
89. 汪海林,邹汉法,孔亮,倪坚毅,张玉奎. 分子生物色谱用于中药 活性成分筛选及质量控制方法的研究. 色谱. 1999,17(2): 123-127
90. Wang H, Zou H, Kong L, Ni J. Analysis of bioactive compounds in traditional Chinese medicines by molecular biochromatography with α 1-acid glycoprotein stationary phase. J. Basic Clin. Physiol. Pharmacol. 2000, 11(2): 155-172
91. Wang H, Zou H, Ni J, Guo B. Comparative separation of biologically active components in Rhizoma Chuanxiong by affinity chromatography withα1-acid glycoprotein and human serum albumin as stationary phase. Chromatographia. 2000, 52: 459-464
92. 孔亮,邹汉法,汪海林,倪坚毅,张玉奎. 以人血清白蛋白为固定 相的分子生物色谱分析几种中药活性成分的研究. 高等学校化学学 报. 2000,21(1): 36-40
93. Sandberg M, Lundahl P. Immobilization of phospholipid vesicles on alkyl derivatives of agarose beads. Biochim. Biophys. Acta. 1987, 924: 185-192
94. Pidgeon C, Venkataram U V. Immobilized artificial membrane chromatography: supports composed of membrane lipids. Anal. Biochem. 1989, 176: 36-47
95. 孙进,王淑君,程刚,陈济民. 磷脂膜色谱及其在生物药剂学中的 应用. 药学学报. 2003, 38(6): 475-480
96. 贺浪冲,杨广德,耿信笃. 固定在硅胶表面细胞膜的酶活性及其色 谱特性. 科学通报. 1999,44(6): 632-637
97. 高琨,贺浪冲,杨广德. 用细胞膜色谱法筛选研究红毛七中的有效 成分. 中国药学杂志. 2003,38(1): 14-16
98. 梁明金,贺浪冲. “四物汤”中当归有效部位及有效成分的研究. 分 析化学. 2004,32(1): 83-86
99. 赵小娟,党高潮,杨广德,贺浪冲. 淫羊藿根与叶活性成分的分析 和比较. 分析化学. 2002: 30(2): 195-197
100. 张汉利,杨广德,贺浪冲,杨银京. 太白花活性成分的筛选与药理 作用相关性研究. 中国药学杂志. 2003,38(2): 92-94
101. 陈蓁,王锐平,贺浪冲,徐迪琴. 细胞膜色谱法筛选红花中的有效 成分. 陕西中医. 2004,25(7): 643-644
102. 王锐平,陈蓁,贺浪冲. 用细胞膜色谱法筛选菟丝子的有效成分. 陕 西中医. 2003,24(6): 553-554
103. Mao X, Kong L, Luo Q, Li X, Zou H. Screening and analysis of permeable compounds in Radix Angelica Sinensis with immobilized liposome chromatography. J. Chromatogr. B. 2002, 779: 331-339104. Mao X, Kong L, Li X, Guo B, Zou H. Unilamellar liposomes covalently coupled on silica gel for liquid chromatography. Anal. Bioanal. Chem. 2003, 375: 550-555
105. 盛亮洪,李睿岩,李萍,邹汉法,孔亮. 固定化脂质体色谱研究中 药复方的细胞膜通透性成分及其质量控制. 分析化学. 2004,32(12): 1595-1598
106. Barbato F, Rotonda M I L, Quaglia F. Interactions of nonsteroidal anti-inflammatory drugs with phospholipids: comparison between octanol/buffer partition coefficients andchromatographic indexes on immobilized artificial membranes. J. Pharm. Sci. 1997, 86(2): 225-229
107. Barbato F, Rotonda M I L, Quaglia F. Chromatographic indexes on immobilized artificial membrane for local anesthetics: relationships with activity data on closed sodium channels. Pharm. Res. 1997, 14(12): 1699-1705
108. Cao X, Lin L, Zhou Y, Zhang W, Shi G, Yamamoto K, Jin L. Study of the interaction of 6-mercaptopurine with protein by microdialysis coupled with LC and electrochemical detection based on functionalized multi-wall carbon nanotubes modified electrode. J. Pharm. Biomed. Anal. 2003, 32 (3): 505-512
109. Yoshitake T, Yoshitake S, Fujino K, Nohta H, Yamaguchi M, Kehr J. High-sensitive liquid chromatographic method for determination of neuronal release of serotonin, noradrenaline and dopamine monitored by microdialysis in the rat prefrontal cortex. J. Neurosci. Methods. 2004, 140(1-2): 163-168
110. Ciriacks C M, Bowser M T. Monitoring D-serine dynamics in the rat brain using online microdialysis-capillary electrophoresis. Anal. Chem. 2004, 76(22): 6582-6587
111. Zou H, Wang H, Zhang Y. Stereoselective binding of warfarin and ketoprofen to HSA determined by microdialysis combined with HPLC. J. Liq. Chromatogr. R. T. 1998, 21(17): 2663-2674
112. Su X, Kong L, Li X, Chen X, Guo M, Zou H. Screening and analysis of bioactive compounds with biofingerprinting chromatogram analysis of traditional Chinese medicines targeting DNA by microdialysis/HPLC. J. Chromatogr. A. 2005, 1076: 118-126
113. Hiriko Iwama ,Sakae Amagaya ,Yukio Ogihara. Effect of Shassaikoto, A Japanese and Chinese herbal medical mixture, on the mitogenic activing of lipopolysaccharide -a new pharmacological testing method. J. Ethnopharmacol, 1987, 211: 45
114. 王力倩,余上才,李仪奎,李悦. 用血清药理学方法研究中药苦参、 仙鹤草的抗肿瘤作用. 中国中医药科技. 1995,2(5): 19-21
115. 杨振江,郭岳峰,丘和明,张惠臣. 髓清丸对HEL 细胞系作用的血 清药理学研究. 中国中医基础医学杂志. 2003,9(6): 430-432, 467
116. Homma M, Oka K, Yamada T, Niitsuma T, Ihto H, Takahashi N. A strategy for discovering biologically active compounds with high probability in traditional Chinese herb remedies: an application of Saiboku-To in bronchial asthma. Anal. Biochem. 1992, 202: 179-186.
117. Homma M, Oka K, Yamada T, Niitsuma T, Thto H, Takahashi N. A strategy for discovering biologically-active compounds with high probability in traditional Chinese herb remedies-an application of saiboku-to in bronchial-asthma. Anal. Biochem. 1992, 202(1): 179-187
118. Homma M, Oka K, Ikeshima K, Takahashi N, Niitsuma T, Fukuda t, Itoh H. Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics. J. Pharm. Pharmacol. 1995, 47(8): 687-692
119. Homma M, Oka K, Taniguchi N, Niitsuma T, Hayashi T. Systematic analysis of post-administrative Saiboku-To urine by liquid chromatography to determine pharmacokinetics of traditional Chinese medicine. Biomed. Chromatogr. 1997, 11: 125–131
120. Li C, Homma M, Oka K. Chromatographic identification of phenolic compounds in human urine following oral administration of the herbal medicines Daisaiko-to and Shosaiko-to. J. Chromatogr. B 1997, 693(1): 191-198
121. Li C, Homma M, Oka K. Characteristics of delayed excretion of flavonoids in human urine after administration of Shosaiko-to, a herbal medicine. Biol. Pharma. Bull. 1998, 21(12): 1251-1257
122. 王瑜,李鹏,齐帜. 高通量筛选与药物创新. 上海医药. 2004,25(2): 67-69
123. 邱峰,姚新生. 中药体内直接物质基础研究的新思路. 中药药理与临 床. 1999,15(3): 1-2
124. 安登魁,现代药物分析选论,北京:中国医药科技出版社,2001. 575-673
125. 张祥芝,姜涛. 肝脏的药物代谢及其与临床的关系研究进展. 中国民 康医学杂志. 2003, 15(1): 51-52;
126. Daly A K, Cholerton S, Gregory W, Idle J R. Metabolic polymorphisms. Pharmac. Ther. 1993, 57: 129-160
127. Swart P, Oelen W, Bruins A, Tepper P, Dezeeuw R. Determination of the dopamine-d2 agonist n-0923 and its major metabolites in perfused rat livers by HPLC UV atmospheric-pressure ionization mass-spectrometry. J. Anal. Toxicol. 1994,18 (2): 71-77
128. Dogterom P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Disp. 1993, 21(4): 699-704
129. Vantklooster G A E, Woutersenvannijnanten F M A, Kolker H J, Noordhoek J, Vanmiert A. Improved high-performance liquid-chromatographic method for the determination of ethylmorphine and its metabolites in microsomal incubations and cell-culture media. J. Chromatogr. B. 1992, 579(1): 158-164
130. Lhoest G, Maton N, Laurent A, Verbeeck R K. Isolation and identification of a FK-506 C-36-C-37 dihydrodiol from erythromycin-induced rabbit liver-microsomes. J. Pharm. Biomed.
Anal. 1994, 12(2): 235-241.
131. 薛明. 药物代谢研究在发展新药中的作用. 中国兽药杂志. 1997, 32(4): 52-55
132. Ari?ns E. J., Excrusions in the field of SAR: a consideration of the past. the present and the future. In Biological Activity and Chemical Structure (ed. by Keverling Buisman J A), Amsterdam: Elsevier, 1972. 1–35
133 Fleisch H, Russell R G G, Pyrophosphate and polyphosphate. In Pharmacology of the Endocrine System and Related Drugs (ed. by Hellar H, Pickering B), New York: Pergamon Press, 1970. 61–100
134. Patchett A A, Haris E, Tristram E W, Wyvratt M J, Wu M T, Taub D, Peterson E R, Ikeler T J, Ten Broeke J, Payne L G, Ondeyka D L, Thorsett E D, Grenlee W J, Lohr N S, Hottsommer R D, Joshua H, Ruyle W V, Rothrock J W, Aster S D, Maycock A L, Robinson F M, Hirschmann R, Sweet C S, Ulm E H, Gross D M, Vassil T C, Stone C A. A new class of angiotensin-converting enzyme inhibitors. Nature 1980, 288: 280–283
135. Bodor N. Soft drugs: strategies for design of safer drugs. In Strategy in Drug Research (ed. by Keverling Buisman J A), Amsterdam: Elsevier, 1982. 137–164
136. Flower R J, Moncada S, Vane J R. Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics (ed. by Gilman A G, Goodman L S, Rall T W, Murad F), New York: Macmillan Publisher, Inc., 1985. 674–715
137. 陈昕,周秋丽,王本祥. 人参皂甙Rbl的肠内菌代谢. 药学学报. 1999, 34(6): 410-414
138 黄教成. 中草药有效成分药物代谢动力学研究的新进展. 中草药. 1989, 20(1): 40-45.
139. 车庆明,黄新立,李艳梅,张坤,赤尾光昭,服部征雄. 黄芩甙的 药物代谢产物研究. 中国中药杂志. 2001,26(11): 768-769
140. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins .7. comparison of the decomposition modes of ginsenoside-Rb1 and ginsenoside-Rb2 in the digestive-tract of rats. Chem. Pharmaceut. Bull. 1991,39(9): 2357-2361
2. 姚新生. 借鉴国际传统药物发展经验推动中药现代化进程. 世界科 学技术-中药现代化. 2002, 4(3):6-12
3. 姚新生,胡柯. 中药复方的现代化研究. 化学进展. 1999,2:192-196
4 Yan X, Zhou J, Xie G.. Traditional Chinese Medicines. Burlington, VT: Ashgate Publishing Co., 2000.
5 Nigel Wiseman. Traditional Chinese Medicine: A Brief Outline. J. Chem. Inf. Comput. Sci. 2002, 42: 445-455
6 汤少梁,王高玲. 点击中药出口. 中国药业. 2002,11(11):8-10
7 王序,李荣芷,韩桂秋. 研究常用中药活性成分途径的探讨. 北京医 学院学报. 1982,14(4):372-375
8 王序,韩桂秋,李荣芷,潘竞先,陈雅研,何云庆,涂馥,王邠, Huang L,Lee C,Sandrino M,Chang M,Shen T. 现代生物分析法 对常用中药的筛选研究. 北京医科大学学报. 1986,18(1):31-36
9 江黎明,李志明,韩宝铬. 神经生长因子受体活性中草药及其成分 的筛选. 中草药. 1994,25(2): 79-81, 105
10 田代真—.“血清药理学”と“血清药化学”——汉方の药理学ガぃ 始まった药物血中浓度测定の新しぃ世界. TDM 研究. 1988,5: 54
11 陈耀祖. 中药复方化学研究策略诹议. 化学进展. 1999,11(2): 188-192
12 Lin H J, Lu Y H A. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol. Rev. 1997, 49(4): 403-449
13 杜冠华,胡娟娟,夏丽娟,黄家学,张均田. 药物筛选的发展与现 状. 药学学报. 1998,33(11):876-879
14 张志琪,张延妮,田振军. 药物筛选模型和技术及其在中药活性成 分研究中的应用. 中国中药杂志. 2003,28(10): 907-910
15 Itokawa H, Takeya K, Mihara K, Mori N, Hamanaka T, Sonobe T, Iitaka Y. Studies on the antitumor cyclic hexapeptides obtained from Rubiae radix. Chem. Pharm. Bull. 1983, 31(4): 1424-1427
16 Enslein K. An overview of structure-activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicol. Ind. Health. 1988, 4: 479-498
17 Johnston M V, Trescher W H, Ishida A, Nakajima W. Novel treatments after experimental brain injury. Semin Neonatol. 2000, 5: 75-86
18 吴镭. 药学科学前沿与发展方向. 北京: 中国医药科技出版社, 2000. 89,118.
19 胡娟娟, 杜冠华. 药物筛选模型研究进展. 基础医学与临床. 2001, 21(4): 302-305
20 鲁春娥,武士华. 转基因动物与药物筛选. 国外医学药学分册. 1997, 24(6): 330-334
21 叶文红. 敲除技术及转基因动物模型在遗传病研究中的应用. 国外 医学遗传学分册. 2002,25(5): 252-255
22 李发荣, 吴臻, 杨建雄. 现代生物技术在中药活性组分筛选中的应 用. 中国中药杂志. 2004,24(11): 1099-1101
23 Mickisch G H, Merlino G T, Galski H, et al. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identificat ion of agents that reverse drug resistance. Proc. Natl.
Acad. Sci. U S A. 1991, 88(1): 547-551
24 Porter G M, Armstrong L, Nielsen L L. Strategy for developing transgenic assays for screening antineoplastic drugs that affect tubulin polymerization. Lab. Anim. Sci. 1995, 45(2):145-150
25 胡愉, 张建民, 王红, 何维. 一种中药方剂对PDAPP 转基因小鼠行 为能力的影响. 中国神经免疫学和神经病学杂志. 2004, 11(1): 17-21
26 朱梅菊, 张红, 郭振球. 新制抗癌方对AFB1染毒的HBV转基因小鼠 肝癌前病变组织PCNA 等表达的影响. 中成药. 2004, 26(8): 682-684
27 徐敏,姜丽丽,梁文权,鲁沁渊. α-细辛醚透皮吸收促进剂的筛选. 中 国临床药学杂志. 2000,9(6): 369-370
28 苏连杰, 马文军,马友辉,张应成,吴波. 鸡胚法筛选具有血管生成 抑制作用中药的实验研究. 中医药信息. 2001,18(3): 65
29 司春峰,魏睦新. 中药促结肠动力作用的筛选研究. 中国中西医结合 消化杂志. 2003,11(6): 346-348
30 张素清,施雪筠. 几种中药保存离体心脏的筛选比较研究. 北京中医 药大学学报. 2003,26(2):39-41
31 Cox B, Denyer J C, Binnie A, Donnelly M C, Evans B, Green D V S, Lewis J A, Mander T H, Merritt A T, Valler M J, Watson S P. Application of high-throughput screening techniques to drug discovery. Prog. Med. Chem. 2000, 37: 83-133
32 张英华,金亚宏,严述常. 几种中药及复方抗肿瘤作用(体外)的实验 研究. 中药药理与临床. 1992,8(4): 7-9
33 张慧珠,杨林,任雷鸣,刘淑梅. 中药活性成分逆转肿瘤细胞多药 耐药作用的体外筛选. 华北煤炭医学院学报. 2003,5(3): 265-267
34 张艳军. 增强原代培养鼠胚脊髓运动神经元活力的中药筛选. 天津 中医学院学报. 2004,23(2): 75-77
35 钱慧林,钟良玉. 热毒清药液抗SARS 病毒细胞模型的实验研究. 中 国中医药科技. 2004,11(4): 214-215
36 Ho T Y, Wu S L, Lai I L, Cheng K S, Kao S T, Hsiang C Y. An in vitro system combined with an in-house quantitation assay for screening hepatitis C virus inhibitors. Antivir. Res. 2003, 58: 199-208
37 Shibata Y, Takahashi H, Ishii Y. A convenient in vitro screening method for predicting in vivo drug metabolic clearance using isolated hepatocytes suspended in serum. Drug Metab. Dispos. 2000, 28(12): 1518-1523
38 任德成,胡娟娟,杜冠华. 内皮细胞损伤筛选模型. 药学学报. 2000, 35(增刊): 44-47
39 Wodnicka M, Guarino R D, Hemperly J J, Timmins M R, Stitt D, Pitner J B. Novel fluorescent technology platform for high throughput cytotoxicity and pro-liferation assays. J. Biomol. Screen. 2000, 5(3): 141-152
40 陈永红,杜冠华. 筛选抗脑缺血药物的神经细胞模型. 药学学报. 2000,35(增刊): 21-24
41 Rowan S J, Sanders J K. Enzyme models: design and selection. Curr. Opin. Chem. Biol. 1997, 1: 483-490
42 Hodder P S, Ruzicka J. A flow injection renewable surface technique for cell-based drug discovery functional assays. Anal. Chem. 1999, 71(6): 1160-1166
43 黄家学,胡娟娟,杜冠华. 5-HT 受体结合物的高通量筛选. 药学学 报. 2000,35(增刊): 53-56
44 尚念勇,胡娟娟,杜冠华. 腺苷A1 受体结合物的高通量筛选. 药学 学报. 2000,35(增刊): 47-49
45 Venkataraman S, Martin S M, Schafer F Q, Buettner G R. Detailed methods for the quantification of nitric oxide in aqueous solutions using either an oxygen monitor or EPR. Free Radical. Bio. Med. 2000, 29(6): 580-585
46. Rees S A. Bioanalytical strategies to support a discovery research programme. J. Pharm. Biomed. Anal. 1996, 14: 1185-1190
47. Gillmor S A, Cohen F E. New strategies for pharmaceutical design. Receptor. 1993, 3(3): 155-163
48.孙秋,杨慧敏,褚红标,李铭刚,文孟良. 筛选新抗生素的方法. 云 南农业科技. 2003,4: 43-45
49. Black J. Drugs from emasculated hormones: the principle of syntopic antagonism. Science. 1989, 245(4917): 486-93
50. Kuntz I D. Structure-based strategies for drug design and discovery. Science. 1992, 257: 1078
51. 付青姐,刘叔文,吴曙光. 药物靶点的选择和验证. 生命科学研究. 2001,5(3 Suppl.): 206-209
52. 陈泽乃. 受体技术与新药开发. 中国药学杂志. 1994,29(6): 362-365
53. Alan D. Drug screening-beyond the bottleneck. Nat. Biotechnol. 1999, 17: 859-863
54. 王序,韩桂秋,李荣芷,潘竞先,陈雅研,何云庆,涂馥,王邠. 现 代生物分析法对常用中药的筛选研究. 中药药理与临床. 1985,10-11
55. 高虹,欧阳克清,郑旭煦,许治良,胡应和,蔡绍皙. 毒蕈胆碱M1 受体激动剂的高通量筛选模型. 中国药理学通报. 2003, 19(7):
776-779
56. 郑旭煦,欧阳克清,高虹,许治良,胡应和,蔡绍皙. 神经介素NMU2R 受体激动剂的高通量筛选模型研究. 中国药学杂志. 2004,39(3): 185-188
57. Yamada H, Oya I, Nagai T, Matsumoto T, Kiyohara H, Omura S. Screening of a-glucosidase II inhibitor from Chinese herbs and its application on the quality control of mulberry bark. Shoyakugaku Zasshi. 1993, 47(1): 47-55
58. Tang W, Sun X, Fang J S, Zhang M, Sucher N J. Flavonoids from Radix Scutellariae as potential stroke therapeutic agents by targeting the second postsynaptic density 95(PSD-95)/disc large/zonula occludens-1(PDZ) domain of PSD-95. Phytomedicine 2004, 11(6): 277-284
59. 唐赟,陈凯先,嵇汝运. 离子通道与药物设计. 药学进展. 1995,19(4): 197-205
60. Numann R, Negulescu P A. High-throughput Screening strategies for cardiac ion channels. Trends Cardiovas. Med. 2001, 11(2): 54-59
61. Xu J, Chen Y, Li M. High-throughput technologies for studying potassium channels-progresses and challenges. Rev. Res. Focus. 2004, 3(1): 32-38
62. 张奕华,彭司勋,华维一. 新药研究开发的进展与展望. 中国药科 大学学报. 1999,30(2): 153-158
63. 马全顺,尹世金,陈素,张凡,刘向明. 血竭总黄酮对小鼠三叉神 经节细胞河豚毒素敏感型钠通道电流的抑制作用. 中南民族大学学 报(自然科学版). 2004,23(3): 5-8
64. Neher E, Sadmann B. The patch clamp technique. J. Sci. Am. 1992, 266(3): 44-52
65.张礼和. 以核酸为作用靶的药物研究. 成都:成都科学出版社,1997. 146
66. Burke W. Genomics as a probe for disease biology. N. Engl. J. Med. 2003, 349(10): 969-974
67. 马云鹏. 480 种中草药提取物在体外对癌细胞DNA 作用模式的初步 研究. 中药通报. 1987,12(2): 56
68.邓沱,宁志强,周玉祥,程京. 生物芯片技术在药物研究与开发中 的应用. 中国新药杂志. 2002,11(1): 23-31
69. Heller R A, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J, Woolley DE, Davis RW. Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc. Natl. Acad. Sci. USA. 1997, 94(6): 2150-2155
70. Jellis C L, Cradick T J, Rennert P, Salinas P, Boyd J, Amirault T, Gray G S. Defining critical residues in the epitope for HIV-neutralizing monoclonal antibody using phage display and peptide array technologies. Gene. 1993,137(1): 63-68
71. Pietu G, Alibert O, Guichard V, Lamy B, Bois F, Leroy E, MariageSamson R, Houlgatte R, Soularue P, Auffray C. Novel gene transcripts preferentially expressed in human muscles revealed by quantitative hybridization of a high density cDNA array. Genome Res.1996, 6: 492-503
72 徐伟文,李文全. 高通量药物靶位基因筛选的策略与方法. 中国药学 杂志. 2002,37(4): 241-244
73. 胡岳山,李杰芬,谭宇蕙. 基因芯片技术在中药研究中的应用. 深圳 中西医结合杂志. 2004,14(1): 56-59
74. 托娅,苏秀兰,路桂荣,辛学东,王文礼,柯杨,包文宇. 基因芯 片在抗肿瘤血管生成中草药相关基因筛选中的研究. 第二军医大学 学报. 2002,23 (3): 273-275
75. 周联,王培训,赖小平,周华. 基因芯片在中药复方研究中的应用. 中 药新药与临床药理. 2002, 13(6): 383-384
76 Watanabe C M H, Wolffram S, Ader P, Rimbach G, Packer L, Maguire JJ, Schultz PG, Gohil K. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci. USA. 2001,98 (12): 6577-6580
77. Li X K, Motwani M, Tong W, Bornmann W, Schwartz G K. Huanglian, a Chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol. Pharmacol. 2000, 58 (6): 1287-1293
78. Hopfinger A J, Duca J S. Extraction of pharmacophore information from high2throughput screens. Curr. Opin. Biotechnol. 2000, 11(1): 97-103
79. Chaiken I M. Analytical affinity chromatography in studies of molecular recognition in biology. J Chromatogr. 1986, 376: 11-32
80. Kaliszan R. Quantitative Structure-Chromatographic Retentionships. NewYork: Wiley, 1987
81. Haginaka J, Seyama C, Murashima T. Retentive and enantioselective properties of ovomucoid-bonded silica columns-Influence of protein purity and isolation method. J. Chromatogr. A. 1995, 704(2): 279-287
82 Domenici E, Bertucci C, Salvadori P, Wainer I W. Use of a human serum albumin-based HPLC CSP for the investigation of protein-binding- detection of the allosteric interaction between Warfarin and Benzodiazepine binding-sites. J. Pharm. Sci. 1991, 80(2): 164-166
83. Wainer I W, Noctor T A G, Domenici E, Jadaud P. Chiral recognition on biopolyner-based HPLC CSPs -a case for multiple interaction sites. ACS Sym. Series. 1991, 471: 141-154
84 周维书,刘泽培等编著,药物相互作用──原理和生化基础,北京: 科学出版社,1990
85. Wang H, Zou H, Zhang Y. Quantitative study of competitive binding of drugs to protein by microdialysis/high performance liquid chromatography. Anal.Chem. 1998, 70: 373-377
86. Huang X, Kong L, Li X, Chen X, Guo M, Zou H. Strategy for Analysis and Screening of Bioactive Compounds in Traditional Chinese Medicines. J. Chromatogr. B. 2005, 812(1-2): 71-84
87. Wang H, Kong L, Zou H, Ni J, Zhang Y. Screening and analysis of biologically active compounds in Angelica sinensis by molecular biochromatography. Chromatographia. 1999, 50(7/8): 439-445
88. Wang H, Zou H, Ni J, Kong L, Gao S, Guo B. Fractionation and analysis of Artemisia capillaries Thunb. by affinity chromatography with human serum albumin as stationary phase. J. Chromatogr. A. 2000, 870: 501-510
89. 汪海林,邹汉法,孔亮,倪坚毅,张玉奎. 分子生物色谱用于中药 活性成分筛选及质量控制方法的研究. 色谱. 1999,17(2): 123-127
90. Wang H, Zou H, Kong L, Ni J. Analysis of bioactive compounds in traditional Chinese medicines by molecular biochromatography with α 1-acid glycoprotein stationary phase. J. Basic Clin. Physiol. Pharmacol. 2000, 11(2): 155-172
91. Wang H, Zou H, Ni J, Guo B. Comparative separation of biologically active components in Rhizoma Chuanxiong by affinity chromatography withα1-acid glycoprotein and human serum albumin as stationary phase. Chromatographia. 2000, 52: 459-464
92. 孔亮,邹汉法,汪海林,倪坚毅,张玉奎. 以人血清白蛋白为固定 相的分子生物色谱分析几种中药活性成分的研究. 高等学校化学学 报. 2000,21(1): 36-40
93. Sandberg M, Lundahl P. Immobilization of phospholipid vesicles on alkyl derivatives of agarose beads. Biochim. Biophys. Acta. 1987, 924: 185-192
94. Pidgeon C, Venkataram U V. Immobilized artificial membrane chromatography: supports composed of membrane lipids. Anal. Biochem. 1989, 176: 36-47
95. 孙进,王淑君,程刚,陈济民. 磷脂膜色谱及其在生物药剂学中的 应用. 药学学报. 2003, 38(6): 475-480
96. 贺浪冲,杨广德,耿信笃. 固定在硅胶表面细胞膜的酶活性及其色 谱特性. 科学通报. 1999,44(6): 632-637
97. 高琨,贺浪冲,杨广德. 用细胞膜色谱法筛选研究红毛七中的有效 成分. 中国药学杂志. 2003,38(1): 14-16
98. 梁明金,贺浪冲. “四物汤”中当归有效部位及有效成分的研究. 分 析化学. 2004,32(1): 83-86
99. 赵小娟,党高潮,杨广德,贺浪冲. 淫羊藿根与叶活性成分的分析 和比较. 分析化学. 2002: 30(2): 195-197
100. 张汉利,杨广德,贺浪冲,杨银京. 太白花活性成分的筛选与药理 作用相关性研究. 中国药学杂志. 2003,38(2): 92-94
101. 陈蓁,王锐平,贺浪冲,徐迪琴. 细胞膜色谱法筛选红花中的有效 成分. 陕西中医. 2004,25(7): 643-644
102. 王锐平,陈蓁,贺浪冲. 用细胞膜色谱法筛选菟丝子的有效成分. 陕 西中医. 2003,24(6): 553-554
103. Mao X, Kong L, Luo Q, Li X, Zou H. Screening and analysis of permeable compounds in Radix Angelica Sinensis with immobilized liposome chromatography. J. Chromatogr. B. 2002, 779: 331-339104. Mao X, Kong L, Li X, Guo B, Zou H. Unilamellar liposomes covalently coupled on silica gel for liquid chromatography. Anal. Bioanal. Chem. 2003, 375: 550-555
105. 盛亮洪,李睿岩,李萍,邹汉法,孔亮. 固定化脂质体色谱研究中 药复方的细胞膜通透性成分及其质量控制. 分析化学. 2004,32(12): 1595-1598
106. Barbato F, Rotonda M I L, Quaglia F. Interactions of nonsteroidal anti-inflammatory drugs with phospholipids: comparison between octanol/buffer partition coefficients andchromatographic indexes on immobilized artificial membranes. J. Pharm. Sci. 1997, 86(2): 225-229
107. Barbato F, Rotonda M I L, Quaglia F. Chromatographic indexes on immobilized artificial membrane for local anesthetics: relationships with activity data on closed sodium channels. Pharm. Res. 1997, 14(12): 1699-1705
108. Cao X, Lin L, Zhou Y, Zhang W, Shi G, Yamamoto K, Jin L. Study of the interaction of 6-mercaptopurine with protein by microdialysis coupled with LC and electrochemical detection based on functionalized multi-wall carbon nanotubes modified electrode. J. Pharm. Biomed. Anal. 2003, 32 (3): 505-512
109. Yoshitake T, Yoshitake S, Fujino K, Nohta H, Yamaguchi M, Kehr J. High-sensitive liquid chromatographic method for determination of neuronal release of serotonin, noradrenaline and dopamine monitored by microdialysis in the rat prefrontal cortex. J. Neurosci. Methods. 2004, 140(1-2): 163-168
110. Ciriacks C M, Bowser M T. Monitoring D-serine dynamics in the rat brain using online microdialysis-capillary electrophoresis. Anal. Chem. 2004, 76(22): 6582-6587
111. Zou H, Wang H, Zhang Y. Stereoselective binding of warfarin and ketoprofen to HSA determined by microdialysis combined with HPLC. J. Liq. Chromatogr. R. T. 1998, 21(17): 2663-2674
112. Su X, Kong L, Li X, Chen X, Guo M, Zou H. Screening and analysis of bioactive compounds with biofingerprinting chromatogram analysis of traditional Chinese medicines targeting DNA by microdialysis/HPLC. J. Chromatogr. A. 2005, 1076: 118-126
113. Hiriko Iwama ,Sakae Amagaya ,Yukio Ogihara. Effect of Shassaikoto, A Japanese and Chinese herbal medical mixture, on the mitogenic activing of lipopolysaccharide -a new pharmacological testing method. J. Ethnopharmacol, 1987, 211: 45
114. 王力倩,余上才,李仪奎,李悦. 用血清药理学方法研究中药苦参、 仙鹤草的抗肿瘤作用. 中国中医药科技. 1995,2(5): 19-21
115. 杨振江,郭岳峰,丘和明,张惠臣. 髓清丸对HEL 细胞系作用的血 清药理学研究. 中国中医基础医学杂志. 2003,9(6): 430-432, 467
116. Homma M, Oka K, Yamada T, Niitsuma T, Ihto H, Takahashi N. A strategy for discovering biologically active compounds with high probability in traditional Chinese herb remedies: an application of Saiboku-To in bronchial asthma. Anal. Biochem. 1992, 202: 179-186.
117. Homma M, Oka K, Yamada T, Niitsuma T, Thto H, Takahashi N. A strategy for discovering biologically-active compounds with high probability in traditional Chinese herb remedies-an application of saiboku-to in bronchial-asthma. Anal. Biochem. 1992, 202(1): 179-187
118. Homma M, Oka K, Ikeshima K, Takahashi N, Niitsuma T, Fukuda t, Itoh H. Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics. J. Pharm. Pharmacol. 1995, 47(8): 687-692
119. Homma M, Oka K, Taniguchi N, Niitsuma T, Hayashi T. Systematic analysis of post-administrative Saiboku-To urine by liquid chromatography to determine pharmacokinetics of traditional Chinese medicine. Biomed. Chromatogr. 1997, 11: 125–131
120. Li C, Homma M, Oka K. Chromatographic identification of phenolic compounds in human urine following oral administration of the herbal medicines Daisaiko-to and Shosaiko-to. J. Chromatogr. B 1997, 693(1): 191-198
121. Li C, Homma M, Oka K. Characteristics of delayed excretion of flavonoids in human urine after administration of Shosaiko-to, a herbal medicine. Biol. Pharma. Bull. 1998, 21(12): 1251-1257
122. 王瑜,李鹏,齐帜. 高通量筛选与药物创新. 上海医药. 2004,25(2): 67-69
123. 邱峰,姚新生. 中药体内直接物质基础研究的新思路. 中药药理与临 床. 1999,15(3): 1-2
124. 安登魁,现代药物分析选论,北京:中国医药科技出版社,2001. 575-673
125. 张祥芝,姜涛. 肝脏的药物代谢及其与临床的关系研究进展. 中国民 康医学杂志. 2003, 15(1): 51-52;
126. Daly A K, Cholerton S, Gregory W, Idle J R. Metabolic polymorphisms. Pharmac. Ther. 1993, 57: 129-160
127. Swart P, Oelen W, Bruins A, Tepper P, Dezeeuw R. Determination of the dopamine-d2 agonist n-0923 and its major metabolites in perfused rat livers by HPLC UV atmospheric-pressure ionization mass-spectrometry. J. Anal. Toxicol. 1994,18 (2): 71-77
128. Dogterom P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Disp. 1993, 21(4): 699-704
129. Vantklooster G A E, Woutersenvannijnanten F M A, Kolker H J, Noordhoek J, Vanmiert A. Improved high-performance liquid-chromatographic method for the determination of ethylmorphine and its metabolites in microsomal incubations and cell-culture media. J. Chromatogr. B. 1992, 579(1): 158-164
130. Lhoest G, Maton N, Laurent A, Verbeeck R K. Isolation and identification of a FK-506 C-36-C-37 dihydrodiol from erythromycin-induced rabbit liver-microsomes. J. Pharm. Biomed.
Anal. 1994, 12(2): 235-241.
131. 薛明. 药物代谢研究在发展新药中的作用. 中国兽药杂志. 1997, 32(4): 52-55
132. Ari?ns E. J., Excrusions in the field of SAR: a consideration of the past. the present and the future. In Biological Activity and Chemical Structure (ed. by Keverling Buisman J A), Amsterdam: Elsevier, 1972. 1–35
133 Fleisch H, Russell R G G, Pyrophosphate and polyphosphate. In Pharmacology of the Endocrine System and Related Drugs (ed. by Hellar H, Pickering B), New York: Pergamon Press, 1970. 61–100
134. Patchett A A, Haris E, Tristram E W, Wyvratt M J, Wu M T, Taub D, Peterson E R, Ikeler T J, Ten Broeke J, Payne L G, Ondeyka D L, Thorsett E D, Grenlee W J, Lohr N S, Hottsommer R D, Joshua H, Ruyle W V, Rothrock J W, Aster S D, Maycock A L, Robinson F M, Hirschmann R, Sweet C S, Ulm E H, Gross D M, Vassil T C, Stone C A. A new class of angiotensin-converting enzyme inhibitors. Nature 1980, 288: 280–283
135. Bodor N. Soft drugs: strategies for design of safer drugs. In Strategy in Drug Research (ed. by Keverling Buisman J A), Amsterdam: Elsevier, 1982. 137–164
136. Flower R J, Moncada S, Vane J R. Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics (ed. by Gilman A G, Goodman L S, Rall T W, Murad F), New York: Macmillan Publisher, Inc., 1985. 674–715
137. 陈昕,周秋丽,王本祥. 人参皂甙Rbl的肠内菌代谢. 药学学报. 1999, 34(6): 410-414
138 黄教成. 中草药有效成分药物代谢动力学研究的新进展. 中草药. 1989, 20(1): 40-45.
139. 车庆明,黄新立,李艳梅,张坤,赤尾光昭,服部征雄. 黄芩甙的 药物代谢产物研究. 中国中药杂志. 2001,26(11): 768-769
140. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins .7. comparison of the decomposition modes of ginsenoside-Rb1 and ginsenoside-Rb2 in the digestive-tract of rats. Chem. Pharmaceut. Bull. 1991,39(9): 2357-2361