抗癌药物溴泰君的药代动力学和毒代动力学研究
|
摘要
本文进行了创新的抗癌药物5-溴粉防己碱(溴泰君)的药代动力学、毒代动力学以及探索性地应用代谢组学方法研究其毒性标志物。本研究是国家973计划“基于功能基因组学的创新药物研究”课题(2004BC518902)和天津市科技发展计划重点项目“代谢组学用于中药安全性和作用机理研究”课题(05YFJZJC01100)的基础研究内容之一。从以下四方面获得了具有科学意义和应用价值的研究结果:
1.建立了大鼠血浆中粉防己碱测定的液相色谱/质谱联用法,该方法快速、灵敏、专署性强,并应用此方法进行粉防己碱单剂量口服给药后在大鼠体内的药代动力学研究,结果显示粉防己碱口服给药的体内代谢过程符合一室模型;
2.建立了大鼠血浆中溴泰君的液相色谱/质谱联用测定方法,并将该方法应用于溴泰君单剂量口服给药后在大鼠体内的药代动力学研究,结果显示溴泰君口服给药后在雌雄大鼠体内代谢存在差异,体内代谢过程均符合一室模型;
3.分别进行了粉防己碱和溴泰君两种药物多剂量单次给药、单剂量多次口服给药在大鼠体内的毒代动力学研究,以及毒理学研究。单剂量毒代动力学研究结果显示粉防己碱和溴泰君在致毒剂量下,在大鼠体内的代谢动力学参数均发生变化;多剂量毒代动力学研究记录了两种药物在体内产生毒性的血药浓度经时变化规律,结果显示,高剂量连续给药后,由于毒性作用,粉防己碱和溴泰君在大鼠体内的代谢动力学行为均发生改变。毒理学研究通过血液生化指标的测定和组织病理切片的观察表明,粉防己碱在毒性剂量下,主要表现为肝脏、肺和脾的损伤,停药6天后,病变并未减轻;溴泰君在毒性剂量下,同样主要表现为肝脏、肺和脾的损伤,其中肝脏毒性作用程度轻于粉防己碱,停药后,病变有所减轻但无统计学意义;
4.分别进行粉防己碱和溴泰君两种药物的初步探索性代谢组学研究,利用液相色谱/质谱联用法的测定方法,使用XCMS统计软件进行数据的处理分析,考察机体分别对粉防己碱和溴泰君的毒性作用产生应激反应所造成的血浆、尿液中内源性代谢产物的经时变化规律;寻找两种药物毒性作用的可能的生物标志物离子,分别在血浆、尿液中找到粉防己碱毒性的生物标志物离子10和18个,溴泰君的生物标志物离子16和17个。结合毒代动力学与毒理学研究结果,验证两种药物的毒性靶器官为肝脏,并为今后进一步毒性机制研究提供信息。
In the present study, traditional Chinese medicine tetrandrine and its 5-bromized derivative bromotetrandrine were studied and evaluated through the combination of pharmacokinetics, toxicokinetics and metabonomincs method by which toxic markers were searched. This study is an important part of National 973 Plan Foundation of China (No. 2004BC518902) and Tianjin Development Plan of Science and Technology (05YFJZJC01100). Results with both scientific and practical significance were listed as follows:
1. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of tetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result showed that the metabolism of tetrandrine in both male and female rats was best fitted to one-compartment model.
2. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of bromotetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result exhibited sexual difference in the pharmacokinetics of bromotetrandrine between male and female rats, though its metabolism in both male and female rats was best fitted to one-compartment model.
3. Single-dose and multi-dose toxicokinetic study, as well as toxicological study of both tetrandrine and bromotetrandrine were done in S.D. rats for evaluating kinetic properties and repeated dose safety for the two drugs. Results of single-dose toxicokinetic studies showed that at the dose that might induce toxicity, kinetic parameters of both tetrandrine and bromotetrandrine changed in rats. Multi-dose toxicokinetic studies recorded the changing states of tetrandrine and bromotetrandrine concentration in rat plasma, and demonstrated that after multiple administration of the two drugs at the dose that might induce toxicity, the metabolism of tetrandrine and bromotetrandrine were both changed in rats. Determination of blood biochemical parameters and tissue pathological slices results showed that both tetrandrine and bromotetrandrine exhibited liver, spleen and lung damage, the degree of all the damage was not alleviated after 6 days’recovery.
4. In the present study, we also did some primary metabonomic study for both tetrandrine and bromotetrandrine. LC-MS was developed for urine and plasma sample determination, and XCMS was exploited for data handling and analysis to research time-related changes of endogenous metabolic responses in rat urine and plasma to tetrandrine and bromotetrandrine stimuli, in order to find biomarkers in biochemical matrix. As a result 10 and 18 promising biomarkers were found in plasma and urine for tetrandrine, respectively. And 16 and 17 for bromotetrandrine in plasma and urine, respectively. Combined with the results of toxicokinetic studies, it was further confirmed that both tetrandrine and bromotetrandrine exhibited hepatotoxicity.
1.建立了大鼠血浆中粉防己碱测定的液相色谱/质谱联用法,该方法快速、灵敏、专署性强,并应用此方法进行粉防己碱单剂量口服给药后在大鼠体内的药代动力学研究,结果显示粉防己碱口服给药的体内代谢过程符合一室模型;
2.建立了大鼠血浆中溴泰君的液相色谱/质谱联用测定方法,并将该方法应用于溴泰君单剂量口服给药后在大鼠体内的药代动力学研究,结果显示溴泰君口服给药后在雌雄大鼠体内代谢存在差异,体内代谢过程均符合一室模型;
3.分别进行了粉防己碱和溴泰君两种药物多剂量单次给药、单剂量多次口服给药在大鼠体内的毒代动力学研究,以及毒理学研究。单剂量毒代动力学研究结果显示粉防己碱和溴泰君在致毒剂量下,在大鼠体内的代谢动力学参数均发生变化;多剂量毒代动力学研究记录了两种药物在体内产生毒性的血药浓度经时变化规律,结果显示,高剂量连续给药后,由于毒性作用,粉防己碱和溴泰君在大鼠体内的代谢动力学行为均发生改变。毒理学研究通过血液生化指标的测定和组织病理切片的观察表明,粉防己碱在毒性剂量下,主要表现为肝脏、肺和脾的损伤,停药6天后,病变并未减轻;溴泰君在毒性剂量下,同样主要表现为肝脏、肺和脾的损伤,其中肝脏毒性作用程度轻于粉防己碱,停药后,病变有所减轻但无统计学意义;
4.分别进行粉防己碱和溴泰君两种药物的初步探索性代谢组学研究,利用液相色谱/质谱联用法的测定方法,使用XCMS统计软件进行数据的处理分析,考察机体分别对粉防己碱和溴泰君的毒性作用产生应激反应所造成的血浆、尿液中内源性代谢产物的经时变化规律;寻找两种药物毒性作用的可能的生物标志物离子,分别在血浆、尿液中找到粉防己碱毒性的生物标志物离子10和18个,溴泰君的生物标志物离子16和17个。结合毒代动力学与毒理学研究结果,验证两种药物的毒性靶器官为肝脏,并为今后进一步毒性机制研究提供信息。
In the present study, traditional Chinese medicine tetrandrine and its 5-bromized derivative bromotetrandrine were studied and evaluated through the combination of pharmacokinetics, toxicokinetics and metabonomincs method by which toxic markers were searched. This study is an important part of National 973 Plan Foundation of China (No. 2004BC518902) and Tianjin Development Plan of Science and Technology (05YFJZJC01100). Results with both scientific and practical significance were listed as follows:
1. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of tetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result showed that the metabolism of tetrandrine in both male and female rats was best fitted to one-compartment model.
2. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of bromotetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result exhibited sexual difference in the pharmacokinetics of bromotetrandrine between male and female rats, though its metabolism in both male and female rats was best fitted to one-compartment model.
3. Single-dose and multi-dose toxicokinetic study, as well as toxicological study of both tetrandrine and bromotetrandrine were done in S.D. rats for evaluating kinetic properties and repeated dose safety for the two drugs. Results of single-dose toxicokinetic studies showed that at the dose that might induce toxicity, kinetic parameters of both tetrandrine and bromotetrandrine changed in rats. Multi-dose toxicokinetic studies recorded the changing states of tetrandrine and bromotetrandrine concentration in rat plasma, and demonstrated that after multiple administration of the two drugs at the dose that might induce toxicity, the metabolism of tetrandrine and bromotetrandrine were both changed in rats. Determination of blood biochemical parameters and tissue pathological slices results showed that both tetrandrine and bromotetrandrine exhibited liver, spleen and lung damage, the degree of all the damage was not alleviated after 6 days’recovery.
4. In the present study, we also did some primary metabonomic study for both tetrandrine and bromotetrandrine. LC-MS was developed for urine and plasma sample determination, and XCMS was exploited for data handling and analysis to research time-related changes of endogenous metabolic responses in rat urine and plasma to tetrandrine and bromotetrandrine stimuli, in order to find biomarkers in biochemical matrix. As a result 10 and 18 promising biomarkers were found in plasma and urine for tetrandrine, respectively. And 16 and 17 for bromotetrandrine in plasma and urine, respectively. Combined with the results of toxicokinetic studies, it was further confirmed that both tetrandrine and bromotetrandrine exhibited hepatotoxicity.
引文
[1] Liu CX, Xiao PG, Li DP, Modern Research and Application of Chinese Medicinal Plants, Hong Kong: Hong Kong Publisher, 2000, 631-637
[2]徐国均,生药学,北京:人民卫生出版社,1997, 332~336
[3] Kwan CY, Chen YY, Tetrandrine,a calcium antagonist of Chinese herbal origin, iner-action with vascular muscle alpha 1-adrenoceptor, Life Sci, 1996, 23: 751～753
[4]熊一力,王宏伟,姚伟星等,粉防己碱对自发性高血压大鼠血管平滑肌细胞增殖及对PDGF-B,BFGF和相关癌基因表达的影响,中国药理学与毒理学杂志,1998, 12(2): l09～ll2
[5]胡文淑,周正航,胡崇家等,粉防己碱对七种血管平滑肌的作用,中国药理学报,1984, 5(4): 257~260
[6]姚伟星,夏国瑾,韩虹等,粉防己碱和维拉帕米对哇巴因对豚鼠血流动力学作用的影响,中国药理学报,1986, 7(2): 128~130
[7]李贵荣,方达超,吕富华,粉防己碱对麻醉兔心内传导系统的影响,中国药理学报,1989, 5(4): 217~210
[8]郭治斌,抗心律失常生物碱的研究进展,中国药理学通报,1995, 11(4): 276~280
[9]李庆平,杨解人,饶曼人,预先给予粉防己碱对大鼠工作心脏缺血再灌注损伤的保护作用,中国药理学与毒理学杂志,1994, 8(2): 114～117
[10]祝武强,曾秋棠,曹林生等,粉防己碱对缺氧和复氧损伤心室肌细胞内Ca2+超载的作用,临床心血管病杂志,2000, 16(2): 83~84
[11]钟宁,钱家庆,M受体机制在粉防己碱保护心脏缺血再灌注损伤作用中的影响,中国药理学通报,2000, 16(3): 282-286
[12] Li SY, Teh BS, Seow WK, et al, Effect of tetrandrine on immunological responses and cardiac transplant rejection in mice, Int Arch Allergy Appl Immunol, 1989, 90: 169~173
[13] Ioannoni B, Chalmers AH, Scow WK, et a1, Tetrandrine and tranmembrane signal transduetion: effect onphos phoinositide metabolism, calcium flux and proteinkinase C transloaction in human lymphocytes, Int Arch Allergy Appl Immunol, 1989, 89: 349~354
[14] Kondo Y, Imai Y, Hojo H, et al, Selective inhibition of T-cell-dependent immune responses by bisbenzylisoquinoline alkaloid in vivo, Int J Immunopharmacol, 1992, 14(7): 1181~1186
[15]万江华,方玉华,粉防己碱的药理与临床应用进展,中国药学杂志,I996, 31(8): 454~456
[16] Castranova V, Kang JH, Joseph, KHM, et al, Effects of isobenzyliso—quioline alkaloid on alveolar macrophages, correlation between binding attinity, inhibitory potency and antifibrotic potentia1, Toxicol Appl Pharmacol, 1991, 108(2): 242~252
[17]孙自勤,王要军,权启镇等,汉防己甲素与秋水仙碱抗肝纤维化作用的比较,中国药理学通报,1996, 12(4): 345～347
[18]李定国,夏维新,陆汉明等,血清Ⅲ型前胶原肽在钙通道阻制荆治疗肝纤维化中的意义,中华内科杂志,1990, 29(8): 453~456
[19]田字彬,刘思良,李定国等,汉防己甲素对血小板衍生生长因子促细胞增殖效应的阻断作用,中华医学杂志,1997, 77(1): 50～53
[20]胡义扬,刘成,刘平,中药有效成分抗肝纤维化研究现状与展望,中草药,1996, 27(3): 183~185
[21] Tian H, Pan QC, A comparative study on effect of two bisbenzylisoquinolines, tetrandrine and berbamine, on reversal of multidrug resistance, Acta Pharmaceutica Sinica 1997, 32(4): 245~250
[22]符立梧,潘启超,黄红兵等,粉防己碱逆转肿瘤多药耐药性细胞的凋亡抗性作用,中国药理学通报,1998, 14(4): 309~311
[23]陈树元,钱忠秀,叶松柏,粉防己碱、硝苯地平和卡托普利对肾性高血压大鼠氧自由基与前列腺素的影响,中国药理学与毒理学杂志,1993, 7(4): 263~265
[24]漆松涛,朱诚,卢亦成等,粉防己碱对脑缺血的保护作用,中国药理学通报,1992, 8(1): 6~
[25] Irving L, Heil BV, Thong YH, Synergy between tetrandrine and FK506 in prevention of diabetes BB rat, Life Sci, 1993, 53: 453~458
[26] Lieberman I, Lentz DP, Trucco GA, et a1, Prevention by tetrandrine of spontaneous development of diabetes mellitus in BB rats, Diabetes, 1992, 41(5): 616~619
[27]孙桂荣,王秀国,汉防己甲素对糖尿病大鼠的降血糖作用,基础医学与临床,1996, 16(3): 222~224
[28]祯晓光,顾丽英,陈桂英等,粉防己碱对鼠脑缺血的作用,中国药理学通报,1997, 13(2): 148~150
[29]王中峰,薛春生,周岐新等,粉防己碱对缺氧所致大鼠皮层神经元钙通道功能变化的影响,中国药理学与毒理学杂志,2000, 14(1): 58~61
[30]钱玲梅,王笑云,冷静,粉防己碱干预大鼠急性缺血再灌注肾损伤中的细胞凋亡变化,中华肾脏病杂志,1998, 14(4): 252～253
[31]钱玲梅,王笑云,冷静,粉防己碱用于大鼠急性缺血性肾损伤的实验观察,中国急救医学,1999, 19(4): 195～196
[32]曾彪,戴闺柱,粉防己碱和维拉帕米对高血压病左室舒缩功能作用的探讨,中华内科杂志,1991, 30(3): 134~137
[33]于世龙,周本才,高浴,汉防己甲素治疗心绞痛,中华内科杂志,1985, 24(11): 682~683
[34]卢焰山,王子群,黄文增,汉防己甲素终止室上性心动过速的临床观察,中华心血管病杂志,1990, 18(3): 164~166
[35]李全路,徐永化,周泽深等,汉防己甲素治疗33例矽肺三年的疗效观察,中华结核和呼吸杂志,1981, 4(6): 321~322
[36]李国定,权启镇,陆玮等,钙通道阻滞剂在肝硬化门脉高压患者中的应用,中华医学杂志,1990, 70(7): 370~374
[37] Li D, Lu H, Li X, Calcium channel blockers in cirrhotic patients with portal hypertension, Chen Med J Engl, 1995, 108: 803~808
[38]李凤前,陆彬,粉防己碱制剂研究进展,中草药,1999, 30(6): 475-477
[39]李凤前,陆彬,陈文彬等,肺靶向汉防己甲素缓释胶囊的长期毒性研究,中国药品标准,2001, 3(4): 45~49
[40] Jin J, Wang FP, Wei H, Reversal of multidrug resistance of cancer through inhibition of P-glycoprotein by 5-bromotetrandrine, Cancer Chemotherapy and Pharmacology 2005, 55: 179~183
[41]刘昌孝,药物评价学,化学工业出版社,2006, 185~188
[42]娄建石,张才丽,粉防己碱在兔体内的药代动力学研究,中草药,1993, 24(1): 24~26
[43]汪宝琪,庞志功,范春,北豆根中粉防己碱的药物代谢动力学研究,西安医科大学学报,1996, 17(4): 498~500
[44]刘月盈,张循范,汪金平等,汉防己甲素的安全性,中国医院药学杂志,1990, 10(6): 204~205
[45] Wong CW, Seow WK, Zeng TS, et al, Comparative immunopharmacology and toxicology of the bisbenzylisoquinoline alkaloids tetrandrine and berbamine, Int J Immunopharmac 1991, 13(5): 579~585
[46] Tainlin L, Tingyi H, Changqi Z, et al, Studies of the chronic toxicity of tetrandrine in dogs: an inhibitor of silicosis, Ecotoxicol Environ Saf, 1982, 6(6): 528~534
[47] Cai Y, Qi XM, Gong LK, et al, Tetrandrine-induced apoptosis in rat primary hepatocytes is initiated from mitochondria: caspases anf endonuclease G (Endo G) pathway, Toxicology, 2006, 218(1): 1~12
[48]肖淑华,魏广力,陆榕,溴泰君与阿霉素单用和联合应用在Beagle犬的毒代动力学研究,中国临床药理学与治疗学,2004, 9(4): 1221~1225
[49] Xiao SH, Wei GL, Lu R, et al, Pharmacokinetics of bromotetrandrine in rats and Beagle dogs. Acta Pharmaceutica Sinica 2004, 39(4): 301-304
[50] Xiao SH, Wei GL, Lu R, et al, Studies on pharmacokinetics of bromotetrandrine in animals (Ⅱ) Effect of coadministration of bromotetrandrine with adriamycin on the pharmacokinetics. Asian Journal of Drug Metabolism and Pharmacokinetics 2004, 4(1): 63-66
[51] Xiao SH, Wei GL, Lu R, et al, Tissue distribution and excretion of bromotetrandrine in rats. Acta Pharmaceutica Sinica 2005, 40(5): 453-456
[52]刘昌孝,药物评价学,化学工业出版社,2006, 287~290
[53] Welling PC, Differences between pharmacokinetics and toxicokinetics, Toxicol Pathol, 1995, 23(2): 143~147
[54] Kitano H, Systems biology: a brief overview, Science, 2002, 295(5560): 1662~1664
[55] Joyce AR, Palsson BO, The model organism as a system: integrating its‘omics’sets, Nat Rev Mol Ceil Biol, 2006, 7(3): 198~210
[56] Nicholson JK, Lindon JC, Holmes E, Metabonomics: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data, Xenobiodca, 1999, 29(11): 1181~1189
[57] Nebert DW, Vesell ES, Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead, Eur J Pharmacol, 2004, 500: 267~280
[58]李伶,颜贤忠,代谢组学在毒理学中的应用进展,军事医学科学院院刊,2007, 31(2): 183-186
[59]陈立娟,彭双清,代谢组学技术及其在毒理学研究领域中的应用,生物技术通讯,2007, 18(1): 149~151
[60]田卫,张海霞,黄华宇等,高效液相色谱法测定大鼠血浆中防己诺林碱和粉防己碱,分析测试技术与仪器,2007, 13(1): 60~63
[61]谭桂山,戴智勇,徐平声等,高效液相色谱法测定人血浆中汉防己甲素,湖南医科大学学报,2000, 25(4): 409~410
[62]黄建明,郭济贤,段更利,RP-HPLC法测定千金藤属植物中7种生物活性生物碱,药学学报,1998, 23(7): 528~533
[63]王天勇,杨文远,反相高效液相色谱测定三种中药中粉防己碱,分析测定技术与仪器,1995, 1(1): 31~34
[64]宋旭峰,余菁,胡晓炜,RP-HPLC测定轻身减肥片中粉防己碱与防己诺林碱的含量,中成药,2005, 27(4): 405~407
[65]何丽一,李宝明,段宏瑾,粉防己中三种双苄基异喹啉生物碱的高效液相色谱法测定,中草药,1994, 25(12): 629~630
[66]吕凌,赵勇,张体珍等,轻燕减肥胶囊质量标准研究,安徽中医学院学报,2000, 19(5): 41~43
[67] Yang JJ, Long H, Liu HW, et al, Analysis of tetrandrine and fangchinoline in traditional Chinese medicines by capillary electrophoresis, J Chromatogr A, 1998, 811(1-2): 274~279
[68] Gao W, Lin S, Chen Y, et al, Nonaqueous capillary electrophoresis for rapid and sensitive determination of fangchinoline and tetrandrine in radix Stephaniae tetrandrae and its medicinal preparations, J Sep Sci, 2005, 28(7): 639~646
[69]陈春林,张才丽,高效液相色谱法测定粉防己碱血浆浓度,中国医院药学杂志,1991, 11(1): 490~492
[70]熊惠瑜,李艳芳,丁岩等,建立离子对高效液相色谱法检测小鼠血浆中粉防己碱浓度的方法,中国临床药理学杂志,2004, 20(1): 56-59
[71]汪宝琪,范春,用胶束荧光法监测粉防己碱的血药浓度,化学通报,1996, 4: 44-45
[72]柳仁民,何凤云,孙爱玲,毛细管电泳-电喷雾-质谱-质谱分离鉴定粉防己生物碱,药学学报,2004, 39(5): 363-366
[73] Koh HL, Wang H, Zhou S, et al, Detection of aristolochic acid I, tetrandrine and fangchinoline in medicinal plants by high performance liquid chromatography and liquid chromatography/mass spectrometry, J Pharm Biomed Anal, 2006, 40: 653~661
[74]孙卉,韩国柱,苏成业等,异汉防己甲素在大鼠体内的药代动力学及组织分布,药学学报,1990, 25(4): 241~246
[75] Igarashi T, Sekido T, Case studies for statistical analysis toxicokinetic data, Regul Toxocol Pharmacol, 1996, 23(3): 193~208
[76] Dahlem AM, Allerheiligen SR, Vodicnik MJ, Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies, Toxicol Pathol, 1995, 23(2): 170~178
[77] Pai SM, Fettner SH, Hajian G, et al, Characterization of AUCs from sparsely sampled populations in toxicology studies, Pharm Res, 1996, 13: 1283~1290
[78] Van Bree J, Application of sparse sampling approaches in rodent toxicokinetics: prospective view, Drug Inf J, 1994, 28: 263~279
[79] Nicholson JK, Wilson ID, Understanding‘global’systems biology: metabonomics and the continuum of metabolism, Nat Rev Drug Discov, 2003, 2(8): 668~676
[80] Lindon JC, Holmes E, Nicholson JK, So what’s the deal with metabonomics? Anal Chem, 2003, 75(17): 384A~391A
[81] Nicholson JK, Connelly J, Lindon JC, et al, Metabonomics: a platform for studying drug toxicity and gene function, Nat Rev Drug Discov, 2002, 1(2): 153~161
[82] Weckwerth W, Morgenthal K, Metabonomics: from pattern recognition to biological interpretation, Drug Discov Today, 2005, 10(22): 1551~1161
[83] Dettmer K, Aronov PA, Hammock BD, Mass spectrometry-based metabolomics, Mass Spectrum Rev, 2007, 26(1): 51~78
[84] Nobeli I, Thornton JM, A bioinformatician’view of metabolome, Bioassays, 2006, 28(5): 534~545
[85] Brindle JT, Antti H, Holmes E, et a1, Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics, Nat Med, 2002, 8(12): 1439~1444
[86] Sabatine MS, Liu E, Morrow DA, et a1, Metabolomic identification of novel biomarkers of myocardial ischemia, Circulation, 2006, 112(25): 3868~3875
[87] Lindon JC, Holmes E, Nicholson JK, Metabonomics techniques and applications to pharmaceutical research&development, Pharm Res, 2006, 23(6): 1075~1088
[88] Verhoeckx K, Bijlsmac S, Jespersend S, et a1, Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis, Int immunopharmacol, 2004, 4(12): 1499~1514
[89] Ebbels T, Keun HC, Beekonert OP, Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach, J Proteome Res, 2007, 6(11): 4407~4422
[90] Wagner C, Sefkow M, Kopka J, Construction and application of a mass spectral and retention time index database generated from plant GC/EI-TOF-MS metabolite profiles, Phytochemistry, 2003, 62(6): 887~900
[2]徐国均,生药学,北京:人民卫生出版社,1997, 332~336
[3] Kwan CY, Chen YY, Tetrandrine,a calcium antagonist of Chinese herbal origin, iner-action with vascular muscle alpha 1-adrenoceptor, Life Sci, 1996, 23: 751～753
[4]熊一力,王宏伟,姚伟星等,粉防己碱对自发性高血压大鼠血管平滑肌细胞增殖及对PDGF-B,BFGF和相关癌基因表达的影响,中国药理学与毒理学杂志,1998, 12(2): l09～ll2
[5]胡文淑,周正航,胡崇家等,粉防己碱对七种血管平滑肌的作用,中国药理学报,1984, 5(4): 257~260
[6]姚伟星,夏国瑾,韩虹等,粉防己碱和维拉帕米对哇巴因对豚鼠血流动力学作用的影响,中国药理学报,1986, 7(2): 128~130
[7]李贵荣,方达超,吕富华,粉防己碱对麻醉兔心内传导系统的影响,中国药理学报,1989, 5(4): 217~210
[8]郭治斌,抗心律失常生物碱的研究进展,中国药理学通报,1995, 11(4): 276~280
[9]李庆平,杨解人,饶曼人,预先给予粉防己碱对大鼠工作心脏缺血再灌注损伤的保护作用,中国药理学与毒理学杂志,1994, 8(2): 114～117
[10]祝武强,曾秋棠,曹林生等,粉防己碱对缺氧和复氧损伤心室肌细胞内Ca2+超载的作用,临床心血管病杂志,2000, 16(2): 83~84
[11]钟宁,钱家庆,M受体机制在粉防己碱保护心脏缺血再灌注损伤作用中的影响,中国药理学通报,2000, 16(3): 282-286
[12] Li SY, Teh BS, Seow WK, et al, Effect of tetrandrine on immunological responses and cardiac transplant rejection in mice, Int Arch Allergy Appl Immunol, 1989, 90: 169~173
[13] Ioannoni B, Chalmers AH, Scow WK, et a1, Tetrandrine and tranmembrane signal transduetion: effect onphos phoinositide metabolism, calcium flux and proteinkinase C transloaction in human lymphocytes, Int Arch Allergy Appl Immunol, 1989, 89: 349~354
[14] Kondo Y, Imai Y, Hojo H, et al, Selective inhibition of T-cell-dependent immune responses by bisbenzylisoquinoline alkaloid in vivo, Int J Immunopharmacol, 1992, 14(7): 1181~1186
[15]万江华,方玉华,粉防己碱的药理与临床应用进展,中国药学杂志,I996, 31(8): 454~456
[16] Castranova V, Kang JH, Joseph, KHM, et al, Effects of isobenzyliso—quioline alkaloid on alveolar macrophages, correlation between binding attinity, inhibitory potency and antifibrotic potentia1, Toxicol Appl Pharmacol, 1991, 108(2): 242~252
[17]孙自勤,王要军,权启镇等,汉防己甲素与秋水仙碱抗肝纤维化作用的比较,中国药理学通报,1996, 12(4): 345～347
[18]李定国,夏维新,陆汉明等,血清Ⅲ型前胶原肽在钙通道阻制荆治疗肝纤维化中的意义,中华内科杂志,1990, 29(8): 453~456
[19]田字彬,刘思良,李定国等,汉防己甲素对血小板衍生生长因子促细胞增殖效应的阻断作用,中华医学杂志,1997, 77(1): 50～53
[20]胡义扬,刘成,刘平,中药有效成分抗肝纤维化研究现状与展望,中草药,1996, 27(3): 183~185
[21] Tian H, Pan QC, A comparative study on effect of two bisbenzylisoquinolines, tetrandrine and berbamine, on reversal of multidrug resistance, Acta Pharmaceutica Sinica 1997, 32(4): 245~250
[22]符立梧,潘启超,黄红兵等,粉防己碱逆转肿瘤多药耐药性细胞的凋亡抗性作用,中国药理学通报,1998, 14(4): 309~311
[23]陈树元,钱忠秀,叶松柏,粉防己碱、硝苯地平和卡托普利对肾性高血压大鼠氧自由基与前列腺素的影响,中国药理学与毒理学杂志,1993, 7(4): 263~265
[24]漆松涛,朱诚,卢亦成等,粉防己碱对脑缺血的保护作用,中国药理学通报,1992, 8(1): 6~
[25] Irving L, Heil BV, Thong YH, Synergy between tetrandrine and FK506 in prevention of diabetes BB rat, Life Sci, 1993, 53: 453~458
[26] Lieberman I, Lentz DP, Trucco GA, et a1, Prevention by tetrandrine of spontaneous development of diabetes mellitus in BB rats, Diabetes, 1992, 41(5): 616~619
[27]孙桂荣,王秀国,汉防己甲素对糖尿病大鼠的降血糖作用,基础医学与临床,1996, 16(3): 222~224
[28]祯晓光,顾丽英,陈桂英等,粉防己碱对鼠脑缺血的作用,中国药理学通报,1997, 13(2): 148~150
[29]王中峰,薛春生,周岐新等,粉防己碱对缺氧所致大鼠皮层神经元钙通道功能变化的影响,中国药理学与毒理学杂志,2000, 14(1): 58~61
[30]钱玲梅,王笑云,冷静,粉防己碱干预大鼠急性缺血再灌注肾损伤中的细胞凋亡变化,中华肾脏病杂志,1998, 14(4): 252～253
[31]钱玲梅,王笑云,冷静,粉防己碱用于大鼠急性缺血性肾损伤的实验观察,中国急救医学,1999, 19(4): 195～196
[32]曾彪,戴闺柱,粉防己碱和维拉帕米对高血压病左室舒缩功能作用的探讨,中华内科杂志,1991, 30(3): 134~137
[33]于世龙,周本才,高浴,汉防己甲素治疗心绞痛,中华内科杂志,1985, 24(11): 682~683
[34]卢焰山,王子群,黄文增,汉防己甲素终止室上性心动过速的临床观察,中华心血管病杂志,1990, 18(3): 164~166
[35]李全路,徐永化,周泽深等,汉防己甲素治疗33例矽肺三年的疗效观察,中华结核和呼吸杂志,1981, 4(6): 321~322
[36]李国定,权启镇,陆玮等,钙通道阻滞剂在肝硬化门脉高压患者中的应用,中华医学杂志,1990, 70(7): 370~374
[37] Li D, Lu H, Li X, Calcium channel blockers in cirrhotic patients with portal hypertension, Chen Med J Engl, 1995, 108: 803~808
[38]李凤前,陆彬,粉防己碱制剂研究进展,中草药,1999, 30(6): 475-477
[39]李凤前,陆彬,陈文彬等,肺靶向汉防己甲素缓释胶囊的长期毒性研究,中国药品标准,2001, 3(4): 45~49
[40] Jin J, Wang FP, Wei H, Reversal of multidrug resistance of cancer through inhibition of P-glycoprotein by 5-bromotetrandrine, Cancer Chemotherapy and Pharmacology 2005, 55: 179~183
[41]刘昌孝,药物评价学,化学工业出版社,2006, 185~188
[42]娄建石,张才丽,粉防己碱在兔体内的药代动力学研究,中草药,1993, 24(1): 24~26
[43]汪宝琪,庞志功,范春,北豆根中粉防己碱的药物代谢动力学研究,西安医科大学学报,1996, 17(4): 498~500
[44]刘月盈,张循范,汪金平等,汉防己甲素的安全性,中国医院药学杂志,1990, 10(6): 204~205
[45] Wong CW, Seow WK, Zeng TS, et al, Comparative immunopharmacology and toxicology of the bisbenzylisoquinoline alkaloids tetrandrine and berbamine, Int J Immunopharmac 1991, 13(5): 579~585
[46] Tainlin L, Tingyi H, Changqi Z, et al, Studies of the chronic toxicity of tetrandrine in dogs: an inhibitor of silicosis, Ecotoxicol Environ Saf, 1982, 6(6): 528~534
[47] Cai Y, Qi XM, Gong LK, et al, Tetrandrine-induced apoptosis in rat primary hepatocytes is initiated from mitochondria: caspases anf endonuclease G (Endo G) pathway, Toxicology, 2006, 218(1): 1~12
[48]肖淑华,魏广力,陆榕,溴泰君与阿霉素单用和联合应用在Beagle犬的毒代动力学研究,中国临床药理学与治疗学,2004, 9(4): 1221~1225
[49] Xiao SH, Wei GL, Lu R, et al, Pharmacokinetics of bromotetrandrine in rats and Beagle dogs. Acta Pharmaceutica Sinica 2004, 39(4): 301-304
[50] Xiao SH, Wei GL, Lu R, et al, Studies on pharmacokinetics of bromotetrandrine in animals (Ⅱ) Effect of coadministration of bromotetrandrine with adriamycin on the pharmacokinetics. Asian Journal of Drug Metabolism and Pharmacokinetics 2004, 4(1): 63-66
[51] Xiao SH, Wei GL, Lu R, et al, Tissue distribution and excretion of bromotetrandrine in rats. Acta Pharmaceutica Sinica 2005, 40(5): 453-456
[52]刘昌孝,药物评价学,化学工业出版社,2006, 287~290
[53] Welling PC, Differences between pharmacokinetics and toxicokinetics, Toxicol Pathol, 1995, 23(2): 143~147
[54] Kitano H, Systems biology: a brief overview, Science, 2002, 295(5560): 1662~1664
[55] Joyce AR, Palsson BO, The model organism as a system: integrating its‘omics’sets, Nat Rev Mol Ceil Biol, 2006, 7(3): 198~210
[56] Nicholson JK, Lindon JC, Holmes E, Metabonomics: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data, Xenobiodca, 1999, 29(11): 1181~1189
[57] Nebert DW, Vesell ES, Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead, Eur J Pharmacol, 2004, 500: 267~280
[58]李伶,颜贤忠,代谢组学在毒理学中的应用进展,军事医学科学院院刊,2007, 31(2): 183-186
[59]陈立娟,彭双清,代谢组学技术及其在毒理学研究领域中的应用,生物技术通讯,2007, 18(1): 149~151
[60]田卫,张海霞,黄华宇等,高效液相色谱法测定大鼠血浆中防己诺林碱和粉防己碱,分析测试技术与仪器,2007, 13(1): 60~63
[61]谭桂山,戴智勇,徐平声等,高效液相色谱法测定人血浆中汉防己甲素,湖南医科大学学报,2000, 25(4): 409~410
[62]黄建明,郭济贤,段更利,RP-HPLC法测定千金藤属植物中7种生物活性生物碱,药学学报,1998, 23(7): 528~533
[63]王天勇,杨文远,反相高效液相色谱测定三种中药中粉防己碱,分析测定技术与仪器,1995, 1(1): 31~34
[64]宋旭峰,余菁,胡晓炜,RP-HPLC测定轻身减肥片中粉防己碱与防己诺林碱的含量,中成药,2005, 27(4): 405~407
[65]何丽一,李宝明,段宏瑾,粉防己中三种双苄基异喹啉生物碱的高效液相色谱法测定,中草药,1994, 25(12): 629~630
[66]吕凌,赵勇,张体珍等,轻燕减肥胶囊质量标准研究,安徽中医学院学报,2000, 19(5): 41~43
[67] Yang JJ, Long H, Liu HW, et al, Analysis of tetrandrine and fangchinoline in traditional Chinese medicines by capillary electrophoresis, J Chromatogr A, 1998, 811(1-2): 274~279
[68] Gao W, Lin S, Chen Y, et al, Nonaqueous capillary electrophoresis for rapid and sensitive determination of fangchinoline and tetrandrine in radix Stephaniae tetrandrae and its medicinal preparations, J Sep Sci, 2005, 28(7): 639~646
[69]陈春林,张才丽,高效液相色谱法测定粉防己碱血浆浓度,中国医院药学杂志,1991, 11(1): 490~492
[70]熊惠瑜,李艳芳,丁岩等,建立离子对高效液相色谱法检测小鼠血浆中粉防己碱浓度的方法,中国临床药理学杂志,2004, 20(1): 56-59
[71]汪宝琪,范春,用胶束荧光法监测粉防己碱的血药浓度,化学通报,1996, 4: 44-45
[72]柳仁民,何凤云,孙爱玲,毛细管电泳-电喷雾-质谱-质谱分离鉴定粉防己生物碱,药学学报,2004, 39(5): 363-366
[73] Koh HL, Wang H, Zhou S, et al, Detection of aristolochic acid I, tetrandrine and fangchinoline in medicinal plants by high performance liquid chromatography and liquid chromatography/mass spectrometry, J Pharm Biomed Anal, 2006, 40: 653~661
[74]孙卉,韩国柱,苏成业等,异汉防己甲素在大鼠体内的药代动力学及组织分布,药学学报,1990, 25(4): 241~246
[75] Igarashi T, Sekido T, Case studies for statistical analysis toxicokinetic data, Regul Toxocol Pharmacol, 1996, 23(3): 193~208
[76] Dahlem AM, Allerheiligen SR, Vodicnik MJ, Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies, Toxicol Pathol, 1995, 23(2): 170~178
[77] Pai SM, Fettner SH, Hajian G, et al, Characterization of AUCs from sparsely sampled populations in toxicology studies, Pharm Res, 1996, 13: 1283~1290
[78] Van Bree J, Application of sparse sampling approaches in rodent toxicokinetics: prospective view, Drug Inf J, 1994, 28: 263~279
[79] Nicholson JK, Wilson ID, Understanding‘global’systems biology: metabonomics and the continuum of metabolism, Nat Rev Drug Discov, 2003, 2(8): 668~676
[80] Lindon JC, Holmes E, Nicholson JK, So what’s the deal with metabonomics? Anal Chem, 2003, 75(17): 384A~391A
[81] Nicholson JK, Connelly J, Lindon JC, et al, Metabonomics: a platform for studying drug toxicity and gene function, Nat Rev Drug Discov, 2002, 1(2): 153~161
[82] Weckwerth W, Morgenthal K, Metabonomics: from pattern recognition to biological interpretation, Drug Discov Today, 2005, 10(22): 1551~1161
[83] Dettmer K, Aronov PA, Hammock BD, Mass spectrometry-based metabolomics, Mass Spectrum Rev, 2007, 26(1): 51~78
[84] Nobeli I, Thornton JM, A bioinformatician’view of metabolome, Bioassays, 2006, 28(5): 534~545
[85] Brindle JT, Antti H, Holmes E, et a1, Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics, Nat Med, 2002, 8(12): 1439~1444
[86] Sabatine MS, Liu E, Morrow DA, et a1, Metabolomic identification of novel biomarkers of myocardial ischemia, Circulation, 2006, 112(25): 3868~3875
[87] Lindon JC, Holmes E, Nicholson JK, Metabonomics techniques and applications to pharmaceutical research&development, Pharm Res, 2006, 23(6): 1075~1088
[88] Verhoeckx K, Bijlsmac S, Jespersend S, et a1, Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis, Int immunopharmacol, 2004, 4(12): 1499~1514
[89] Ebbels T, Keun HC, Beekonert OP, Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach, J Proteome Res, 2007, 6(11): 4407~4422
[90] Wagner C, Sefkow M, Kopka J, Construction and application of a mass spectral and retention time index database generated from plant GC/EI-TOF-MS metabolite profiles, Phytochemistry, 2003, 62(6): 887~900