乌头类双酯型生物碱的体内代谢研究
|
摘要
乌头类中药川乌、草乌、附子均为中国药典收录的传统的中药,它们的主要活性成分和毒性成分均为乌头碱、中乌头碱和次乌头碱等C19双酯二萜型乌头类双酯型生物碱。因此,研究三种乌头类双酯型生物碱在体内代谢和组织分布,对于阐明乌头类中药药理学毒理学作用机理,指导临床合理用药具有重要意义。
本论文研究了乌头碱、中乌头碱和次乌头碱质谱裂解规律,建立了基于LC/MSn的结构鉴定方法,从三种乌头类双酯型生物碱质谱裂解规律中找出了与结构特异性相关的“诊断离子”,对主要活性基团的电离活性进行排序,并将其用于代谢产物的结构鉴定。
在上述研究的基础上,对这三种乌头类双酯型生物碱的体内代谢产物进行了结构鉴定,从家兔消化道内容物中发现了97种代谢产物,其中乌头碱有15类33个代谢产物;中乌头碱的32种代谢产物均可从乌头碱的代谢产物找到分子量相差14的对应化合物,次乌头碱的32种代谢产物也都能从乌头碱的代谢产物找到分子量相差30的对应化合物,说明这三种生物碱具有基本相同的代谢规律。其中65种代谢产物尚未见报道。
采用液相色谱和三重四极杆型质谱联用仪,优化色谱和质谱条件,选用MRM模式,建立了测定动物组织中乌头碱、中乌头碱和次乌头碱的液相色谱?串联质谱(LC/MS/MS)法。并考察了组织中这三种乌头类双酯型生物碱的分布情况,结果表明,三种生物碱均主要集中在胆和肝脏内,在脾、肾、心、肺、脑中也有分布,三种生物碱在脏器中的浓度由大到小依次为胆、肝、脾、肾、心、肺、脑。
Radix Aconiti, Radix Aconiti Kusnezoffii and Radix Aconiti Lateralis Preparata are traditional Chinese herbs which have extensive activities in anti-inflammatory, abirritation and anti-rheumatism. At the same time, they are well known for their acute and high toxicity, for example, in the causation of severe arrhythmias leading to death. Aconitine, Mesaconitine and Hypaconitine are pharmacologically improved to be the main active ingredients and toxic ingredients as well in the herbs. So, it is very necessary to research the metabolism and distribution of Aconitine, Mesaconitine and Hypaconitine. The aim of this work is to investigate the Metabolism and tissue distribution of them in vivo using the advanced LC/MSn and LC/MS/MS methods.
1 The fragmentation pathway of Aconitine, Mesaconitine and Hypaconitine
This work explained formation of main diagnostic fragment ions by using LCQ mass spectrometer and shown that [M+H-60]+ was specifically relevant to C8-acetoxyl group, [M+H-18]+ to C3-hydroxyl group and [M+H-60-32-28]+ to C15-hydroxyl group. At the same time, we also discuss the fragmentation sequence of main groups and deduced that C8-acetoxyl group is the first active group in fragmentation, C1-methoxy group the second and C6- methoxy group the third。
2 Identification of the metabolites of Aconitine, Mesaconitine and Hypaconitine in rabbits The characteristic fragmentation of Aconitine, Mesaconitine or Hypaconitine were
obtained by analyzing their behavior in multi-stage MS(Msn). The fragmentation pathways can provide theoretical support to help us to identify the infinite structure of metabolites. Metabolites in the gastrointestinal tract, feces, urine and bile of rabbits administrated a single oral dose of 2mg·Kg-1 Aconitine, Mesaconitine or Hypaconitine were investigated respectively. A total of 97 metabolites were found except the unchanged drug. A number of 33 metabolites of aconitine were analyzed in 15 kinds as fellows: (1)Metabolites which MW less 14 than aconitine (aMD14-1～aMD14-6), we deduced that aMD14-1, aMD14-3 or aMD14-6 were demethylate of methoxy group in C1, C6 or C16; aMD14-2 and aMD14-4, one was demethylate of methoxy group in C18 and the other can not be identified; aMD14-5 was 8-formyl-14-benzoyl-aconine. (2)Metabolites which MW more 16 than aconitine (aM_(P16-1)～aMP16-6), we deduced that aM_(P16-1) or aM_(P16-3) were 3′-hydroxyl aconitine or 4′-hydroxyl aconitine; aMP16-6 was 2′-hydroxyl aconitine; aMP16-4和aMP16-5 can not be identified; aM_(P16-2) may be a produce of hydroxylation occurred in methoxy group. (3)Metabolite which MW less 42 than aconitine (aMD42), we deduced it as 14-benzoyl-aconine. (4)Metabolite which MW less 104 than aconitine (aMD104), we deduced it as 8-acetyl -aconine. (5)Metabolites which MW less 30 than aconitine (aMD30-1～aMD30-5), aMD30-3 was deduced as indaconitien, aMD30-5 was deduced as deoxyaconitine and others can not be identified. (6)Metabolite which MW more 28 than aconitine (aMP28), we deduced it as 8- butyryl -aconine. (7)Metabolites which MW more 30 than aconitine (aMP30-1, aMP30-2). Their structures can not be deduced. (8)Metabolites which MW more 182 than aconitine (aMP182-1 , aMP182-2). They were deduced as 8-pentadecanoyl-14-benzoyl-aconine or 8- (13-methyl-tetradecanoyl)-14-benzoyl- aconine. (9)Metabolites which MW more 196 than aconitine (aMP196-1, aMP196-2). They were deduced as 8-palmityl -14-benzoyl-aconine or 8–(14-methyl-pentadecanoyl)-14-benzoyl- aconine. (10)Metabolite which MW more 224 than aconitine (aMP224). It was deduced as 8-stearoyl-14-benzoyl-aconine. (11)Metabolites which MW more 316 than aconitine (aMP316-1 and aMP316-2). Their structures can not be deduced. (12)Metabolites which MW more 168 than aconitine (aMP168-1, aMP168-2). They were deduced as 8-myristoyl-14-benzoyl- aconine or 8-(12-methyl-tridecanoyl)-14-benzoyl-aconine. (13)Metabolite which MW more 218 than aconitine (aMP218). It was deduced as 8-linolenoyl-14-benzoyl-aconine. (14)Metabolite which MW more 220 than aconitine (aMP220). It was deduced as 8–linoleoyl- 14-benzoyl-aconine. (15) metabolites which MW more 222 than aconitine (aMP222-1, aMP222-2). It was deduced as 8–oleoyl-14-benzoyl-aconine or 8-(11-methyl- jecericanoyl)- 14-benzoyl-aconine. Mesaconitine and Hypaconitine have the similar metabolism pathways with the Aconitine, and their metabolites were identified by analyzing the chromatography and mass spectra and comparing with reference substance.
3 Tissue distribution of Aconitine, Mesaconitine and Hypaconitine in rabbits
A sensitive LC/MS/MS method was development with MRM mode to simultaneously determine Aconitine, Mesaconitine and Hypaconitine in biological samples of rabbits. The tissue distribution of Aconitine, Mesaconitine and Hypaconitine was investigated at 4 h Post-dose in rabbits. The result shows that the order of the concentration of Aconitine, Mesaconitine and Hypaconitine for high level to light level in the seven main tissues all are: gallbladder, liver, spleen, kidney, heart, lung, brain.
本论文研究了乌头碱、中乌头碱和次乌头碱质谱裂解规律,建立了基于LC/MSn的结构鉴定方法,从三种乌头类双酯型生物碱质谱裂解规律中找出了与结构特异性相关的“诊断离子”,对主要活性基团的电离活性进行排序,并将其用于代谢产物的结构鉴定。
在上述研究的基础上,对这三种乌头类双酯型生物碱的体内代谢产物进行了结构鉴定,从家兔消化道内容物中发现了97种代谢产物,其中乌头碱有15类33个代谢产物;中乌头碱的32种代谢产物均可从乌头碱的代谢产物找到分子量相差14的对应化合物,次乌头碱的32种代谢产物也都能从乌头碱的代谢产物找到分子量相差30的对应化合物,说明这三种生物碱具有基本相同的代谢规律。其中65种代谢产物尚未见报道。
采用液相色谱和三重四极杆型质谱联用仪,优化色谱和质谱条件,选用MRM模式,建立了测定动物组织中乌头碱、中乌头碱和次乌头碱的液相色谱?串联质谱(LC/MS/MS)法。并考察了组织中这三种乌头类双酯型生物碱的分布情况,结果表明,三种生物碱均主要集中在胆和肝脏内,在脾、肾、心、肺、脑中也有分布,三种生物碱在脏器中的浓度由大到小依次为胆、肝、脾、肾、心、肺、脑。
Radix Aconiti, Radix Aconiti Kusnezoffii and Radix Aconiti Lateralis Preparata are traditional Chinese herbs which have extensive activities in anti-inflammatory, abirritation and anti-rheumatism. At the same time, they are well known for their acute and high toxicity, for example, in the causation of severe arrhythmias leading to death. Aconitine, Mesaconitine and Hypaconitine are pharmacologically improved to be the main active ingredients and toxic ingredients as well in the herbs. So, it is very necessary to research the metabolism and distribution of Aconitine, Mesaconitine and Hypaconitine. The aim of this work is to investigate the Metabolism and tissue distribution of them in vivo using the advanced LC/MSn and LC/MS/MS methods.
1 The fragmentation pathway of Aconitine, Mesaconitine and Hypaconitine
This work explained formation of main diagnostic fragment ions by using LCQ mass spectrometer and shown that [M+H-60]+ was specifically relevant to C8-acetoxyl group, [M+H-18]+ to C3-hydroxyl group and [M+H-60-32-28]+ to C15-hydroxyl group. At the same time, we also discuss the fragmentation sequence of main groups and deduced that C8-acetoxyl group is the first active group in fragmentation, C1-methoxy group the second and C6- methoxy group the third。
2 Identification of the metabolites of Aconitine, Mesaconitine and Hypaconitine in rabbits The characteristic fragmentation of Aconitine, Mesaconitine or Hypaconitine were
obtained by analyzing their behavior in multi-stage MS(Msn). The fragmentation pathways can provide theoretical support to help us to identify the infinite structure of metabolites. Metabolites in the gastrointestinal tract, feces, urine and bile of rabbits administrated a single oral dose of 2mg·Kg-1 Aconitine, Mesaconitine or Hypaconitine were investigated respectively. A total of 97 metabolites were found except the unchanged drug. A number of 33 metabolites of aconitine were analyzed in 15 kinds as fellows: (1)Metabolites which MW less 14 than aconitine (aMD14-1～aMD14-6), we deduced that aMD14-1, aMD14-3 or aMD14-6 were demethylate of methoxy group in C1, C6 or C16; aMD14-2 and aMD14-4, one was demethylate of methoxy group in C18 and the other can not be identified; aMD14-5 was 8-formyl-14-benzoyl-aconine. (2)Metabolites which MW more 16 than aconitine (aM_(P16-1)～aMP16-6), we deduced that aM_(P16-1) or aM_(P16-3) were 3′-hydroxyl aconitine or 4′-hydroxyl aconitine; aMP16-6 was 2′-hydroxyl aconitine; aMP16-4和aMP16-5 can not be identified; aM_(P16-2) may be a produce of hydroxylation occurred in methoxy group. (3)Metabolite which MW less 42 than aconitine (aMD42), we deduced it as 14-benzoyl-aconine. (4)Metabolite which MW less 104 than aconitine (aMD104), we deduced it as 8-acetyl -aconine. (5)Metabolites which MW less 30 than aconitine (aMD30-1～aMD30-5), aMD30-3 was deduced as indaconitien, aMD30-5 was deduced as deoxyaconitine and others can not be identified. (6)Metabolite which MW more 28 than aconitine (aMP28), we deduced it as 8- butyryl -aconine. (7)Metabolites which MW more 30 than aconitine (aMP30-1, aMP30-2). Their structures can not be deduced. (8)Metabolites which MW more 182 than aconitine (aMP182-1 , aMP182-2). They were deduced as 8-pentadecanoyl-14-benzoyl-aconine or 8- (13-methyl-tetradecanoyl)-14-benzoyl- aconine. (9)Metabolites which MW more 196 than aconitine (aMP196-1, aMP196-2). They were deduced as 8-palmityl -14-benzoyl-aconine or 8–(14-methyl-pentadecanoyl)-14-benzoyl- aconine. (10)Metabolite which MW more 224 than aconitine (aMP224). It was deduced as 8-stearoyl-14-benzoyl-aconine. (11)Metabolites which MW more 316 than aconitine (aMP316-1 and aMP316-2). Their structures can not be deduced. (12)Metabolites which MW more 168 than aconitine (aMP168-1, aMP168-2). They were deduced as 8-myristoyl-14-benzoyl- aconine or 8-(12-methyl-tridecanoyl)-14-benzoyl-aconine. (13)Metabolite which MW more 218 than aconitine (aMP218). It was deduced as 8-linolenoyl-14-benzoyl-aconine. (14)Metabolite which MW more 220 than aconitine (aMP220). It was deduced as 8–linoleoyl- 14-benzoyl-aconine. (15) metabolites which MW more 222 than aconitine (aMP222-1, aMP222-2). It was deduced as 8–oleoyl-14-benzoyl-aconine or 8-(11-methyl- jecericanoyl)- 14-benzoyl-aconine. Mesaconitine and Hypaconitine have the similar metabolism pathways with the Aconitine, and their metabolites were identified by analyzing the chromatography and mass spectra and comparing with reference substance.
3 Tissue distribution of Aconitine, Mesaconitine and Hypaconitine in rabbits
A sensitive LC/MS/MS method was development with MRM mode to simultaneously determine Aconitine, Mesaconitine and Hypaconitine in biological samples of rabbits. The tissue distribution of Aconitine, Mesaconitine and Hypaconitine was investigated at 4 h Post-dose in rabbits. The result shows that the order of the concentration of Aconitine, Mesaconitine and Hypaconitine for high level to light level in the seven main tissues all are: gallbladder, liver, spleen, kidney, heart, lung, brain.
引文
[1]冯年平,狄斌,刘文英.药物代谢研究与中药现代化[J].世界科学技术—中医药现代化, 2003, 5(2): 5-7.
[2]史向国.必特螺旋霉素体内代谢与药物动力学研究[D].沈阳:沈阳药科大学, 2003.
[3]王广基.药物代谢动力学[M].北京;化学工业出版社, 2005.
[4]刘睿,谢跃生,潘桂湘,等.药物组织蛋白结合率测定方法的研究进展[J].天津中医药, 2007, 24(6): 526-528
[5] Akimasa S, Nobuko I, Tomoko K, et al. Plasma protein binding study of oxybutynin by high-performance frontal analysis[J]. Journal of Chromatography B, 2002, 768, 1: 177-188 .
[6] Sonu S S. Measurement of drugrotein binding by immobilized human serum albumin-HPLC and comparison with ultrafiltration[J]. Journal of Chromatography B, 2006, 834: 108-116.
[7]周艳钢,李焕德.体内药物代谢研究的意义与应用[J].中南药学, 2009, 17(1): 46-50.
[8]阿基业,王广基.药物代谢研究与药物设计及结构修饰[J].药学进展, 2002, 26(2): 80-86.
[9] Kazmaier S, Hanekop G G, Buher W, et a1. Myocardial consequences of remifentanil in patients with coronary artery disease[J]. J-Anaesth, 2000, 84(5): 578-583.
[10]王淑月,尹宏军,陈竞洪.软药原理与新药设计[J].河北工业科技, 2004, 21(1):58-60.
[11] Bodor N, Buchwald P. Soft drug design: general principles and recent applications[J]. Med Res Rev, 2000, 20(1): 58-101.
[12] Baillie T A. Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism [J].Chem Res Toxicol, 2008, 21(1): 129-137.
[13] Naito S, Furuta S, Yoshida T, et al. Current opinion: Safety evaluation of drug metabolites in development of pharmaceuticals[J]. J Toxicol Sci, 2007, 32(4): 329-341.
[14]王爱国.国内外药物不良反应监测发展概况[J].中国临床药理学杂志, 2009, 25(1): 75-77.
[15] Henz B M. The pharmacologic profile of desloratadine: a review[J]. Allergy, 2001,56(Suppl): 7-13.
[16]马道铭,徐文严.抗组胺新药--盐酸非索那定[J].国外医学皮-肤性病学分册, 1999, 25(3): 129-131.
[17]柴士伟,潘桂湘.药物代谢研究方法简述[J].天津中医药, 2006, 23, (1): 83-85.
[18]谈恒山,张海霞,方芸,等.近10年国内药物体外代谢研究进展[J].江苏药学与临床研究, 2006, 14(5): 297-300.
[19]王佳.药物体外肝代谢研究方法[J].代百东亚太传统医药, 2008, 4(3): 48-50.
[20]郑维思,陈一岳.体外肝代谢系统的研究与应用[J].广东药学院学报, 2007, 23(2): 225-228.
[21]韩聚强,刘树贤.体外肝细胞培养技术新进展[J].河北医科大学学报, 2002, 23(3): 185-187.
[22]邹文,周文.药物代谢的种属和性别差异研究[J].齐鲁药事, 2007, 26(12): 735-737.
[23]王羽,柳晓泉,王广基.药物的肝外代谢[J].药学进展, 2004, 28(7): 289-294.
[24] Ayrton A, Morgan P. Role of transport proteins in drug absorption, distribution and excretion[J]. Xenobiotica, 2001, 31(8-9): 469-497.
[25] Lin J, Yao L, Lame M, et al. The increased emphasis of ADME properties in hit-to-lead drug discovery[J]. Acta Pharmacol Sin, 2006, 27(suppl 1): 226-229.
[26] Obach R S, Baxter J Q, Liston T E, et al. The predietion of human phannacokineic parameters from preclinical and in vitro metabolism data[J]. J.Pharmacol.Exp.Ther, 1997, 283: 46-58 .
[27]胡灵,陈汇.药物代谢动力学在药物研究中的应用与进展(上)[J].中国药师, 2006, 8(5): 651-653.
[28]胡灵,陈汇.药物代谢动力学在药物研究中的应用与进展(上)[J].中国药师, 2007, 10(7): 654-658.
[29]裴利霞,杜冠华.药物代谢动力学研究进展[J].中国医药导刊, 2006, 8(5): 328-329.
[30]索晴,刘树民.近年来中药在肠内的吸收代谢研究方法与思路概述[J].中国中医药科技, 2007, 14(2): 141-142.
[31]董红林,蔡军伟,杨晶.研究小肠吸收的常用方法医医学医学[J].医学研究通讯, 1999, 28(12): 28-29.
[32]李高,方超.药物肠道吸收的生物学研究方法[J].中国药学杂志, 2002, 37, (10):726-729.
[33]水文波.中药活性成分的小肠吸收研究[D].杭州:浙江大学药学院药物信息学研究所, 2006.
[34]程锦,狄留庆.在体肠段灌流模型在中药吸收研究中的应用[J].中国中医药信息杂志, 2008, 15(2): 98-100.
[35]中华人民共和国卫生部药政管理局.现代实用本草(上册)[M].北京:人民卫生出版社, 1997.
[36]中国药品生物制品检验所.中国民族药志[M].北京:人民卫生出版社, 1990.
[37]国家中医药管理局.中华草本(第3册)[M].上海:上海科学技术出版社, 1999.
[38]汪沪双.乌头碱抗风湿作用的药效学研究概述[J].基层中药杂志, 1996, 10, (3): 45-46.
[39]杨姝,金振辉,羊晓东,等.乌头属植物的化学成分及药理作用研究进展[J].云南农业大学学报, 2007, 22(12): 293-295.
[40]蒙其淼,梁洁,吴桂凡,等.生物碱类化合物药理作用研究进展[J].时珍国医国药, 2003, 14 (11): 700-702.
[41]王文祥.现代中药药理学[M].天津:天津科学技术出版社, 1997.
[42]沈映君.中药药理学[M].北京:人民卫生出版社, 2000.
[43]王雅贤,贾宽,张德山,等.乌头碱对小鼠免疫功能影响的实验研究[J].中医药信息, 1989, 5(5): 40-42.
[44]宋东江,陆满文,彭建中.乌头碱类化合物抗炎作用研究进展[J].中草药, 1990, 21(11): 43-45.
[45]林凌云,陈巧鸿,王锋鹏.去甲二萜生物碱的药理活性[J].华西药学杂志, 2004, 19(3): 200-205.
[46]唐希灿,冯洁. 3-乙酰乌头碱氢溴酸盐的镇痛和局部麻醉作用[J].中国药理学报, 1981, 2(1): 82-84.
[47]周远鹏,刘文化,曾贵云.乌头碱及其类似物的毒性和对心脏收缩功能的影响[J].药学学报, 1984, 19(9): 641-646.
[48]周远鹏.附子及其主要成分的药理作用和毒性[J].药学学报, 1983, 18(5): 394-400.
[49]张为亮,徐楚江,杨明,等.附子毒效关系的实验研究[J].广西中医药, 1997,20(3): 43-44.
[50] Yunusov M S. Diterpenoid alkaloids[J]. Nat Prod Rep 1993, 10(5): 471-486.
[51]王锋鹏.乌头属和翠雀属植物中生物碱化学研究概况[J].药学学报, 1981, 16(12): 943-959.
[52]梁笑天.我国二萜生物碱化学的最近进展[J].有机化学, 1986, 5: 335-340.
[53] Pelletier S W, Page S W. Diterpenoid alkaloids[J]. Nat Prod Rep, 1984, 1: 375-381.
[54]彭波,杨华元.乌头、附子及其主要生物碱研究进展[J].华西药学杂志, 1993, 8(3): 158-161.
[55]萧培根,王文采.中国毛茛科药用植物的研究Ⅱ.乌头属的药用植物[J].药学学报, 1965, 12(10): 683-703.
[56]符华林.我国乌头属药用植物的研究概况[J].中药材, 2004, 27(2): 149-152.
[57]肖培根,王锋鹏,高峰,等.中国乌头属植物药用亲缘学研究[J].植物分类学报, 2006, 44(1) 1-46.
[58]李娅萍,田颂九,王国荣.乌头类药物的化学成分及分析方法概况[J].中国中药杂志, 2001, 26(10): 659-662.
[59]陈信义,李峨,侯丽,等.乌头类双酯型生物碱研究进展与应用前景评述[J].中国中医药信息杂志, 2004, 11(10): 922-923.
[60]高黎明,郑尚珍,沈序维,等.乌头属植物中二萜生物碱研究进[J].西北师范大学学报, 1999, 35(2): 109-116.
[61]高黎明,毛学峰,魏小梅,等.二萜类生物碱的药理作用及构效关系研究概况[ J ].西北师范大学学报, 1999, 35(1): 98-103.
[62]张宏贵,史向国,孙莹,等.兔血液中乌头碱代谢产物的研究[J].吉林大学学报(理学版), 2006, 44(2): 284-286.
[63]张宏贵.毒性乌头生物碱代谢产物研究[D].长春:吉林大学药学院, 2006.
[64] Zhang H G, Shi X G S, Sun Y, et al. New Metabolites of Aconitine in Rabbit Urine Chinese Chemical Letters[J]. 2002, 13(8): 758-760.
[65]张宏贵,滕坤,刘永刚,等. LC-MSn分析新乌头碱在兔尿液中的代谢产物[J].中国法医学杂志, 2007, 22(6): 401-402.
[66] Zhang H G, Sun Y, Duan M Y, et al. Separation and identification of Aconitum alkaloids and their metabolites in human urine[J]. Toxicon, 2005, 46: 500-506.
[67] Xie F M, Wang H C, Shu H L, et al. Separation and characterization of the metabolicproducts of lappaconitine in rat urine by high-performance liquid chromatography[J]. Journal of Chromatography BiomedicalApplications, 1990, 526: 109-112.
[68] Yoshioka N, Gonmori K, Tagashira A, et al. A case of aconitine poisoning with analysis of aconitine alkaloids by GC/SIM [J]. ForensicScience International, 1996, 81: 117-120.
[69]孙莹,张宏桂,史向国,等.兔体内乌头碱代谢产物研究[J].药学学报, 2002, 37(10): 781-783.
[70]孙莹,张群书,董丽丹,等.乌头属中药中主要生物碱在不同性别家兔尿中的代谢产物[J].吉林大学学报(理学版), 2007, 45(6): 1032-1034.
[71]王朝虹,文静,陈义华,等.液相色谱质谱联用测定乌头碱在家兔体内代谢产物中国法医学杂志[J], 2006, 21(2): 88-90.
[72]艾路,孙莹,张宏桂.复方中药中乌头生物碱在人体内的代谢产物[J].北京中医药大学学报. 2007, 30(6): 417-422.
[73]李文东.乌头碱体内代谢产物分析方法研究[D].北京:中国医科科学院和北京协和医科大学, 2001.
[74] Wang Y G, Wang S Q , Liu Y X, et al. Characterization of metabolites and cytochrome P450 isoforms involved in the microsomal metabolism of aconitine[J]. Journal of Chromatography B, 2006, 844: 292-300.
[75]赵宇峰,宋凤瑞,国新华,等.利用软电离质谱技术研究乌头碱在肠内细菌中的生物转化[J].高等学校化学学报, 2008, 29(1): 55-59.
[76]赵宇峰,宋凤瑞,越皓,等. 16-O-去甲基去氧乌头碱在肠内细菌中的生物转化研究[J].分析化学, 2007, 35(12): 1711-1715.
[77]赵宇峰,宋凤瑞,王曦烨,等. 16-O-去甲基乌头碱的生物转化及电喷雾质谱研究[J].化学学报, 2008, 66(5): 525-530.
[78]赵宇峰,宋凤瑞,越皓,等.乌头碱的代谢产物去氧乌头碱的生物转化及其电喷雾串联质谱[J]. 2007, 28(11): 2051-2055.
[79] Kentaro W, Makoto N, Hideyuki H, et al. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice[J]. Forensic Science International, 2005, 148: 21-29.
[80]李锐,晏亦林,周莉玲,等.四逆汤的药动学研究[J].中成药, 2002, 24(10): 777-780.
[81]晏亦林.四逆汤有效部位的药代动力学-药效动力学研究[D].广州:广州中医药大学, 2001.
[82]肖凤霞,周莉玲,李锐,等.血药浓度法测定四逆汤制剂中乌头生物碱的药动学参数[J].广州中医药大学学报, 2001, 18(3): 243-246.
[83]王朝虹,文蛟,何毅.液相色谱-质谱联用测定乌头碱血药浓度及其药代动力学参数的方法学研究[J].分析测试学报, 2004, 23(增): 51-54.
[84]李文东,马辰.口服制川乌提取物后家兔体内乌头类双酯型生物碱的组织分布[J].药学学报, 2005, 40(6): 539 -543.
[85]李文东,马辰.高效液相色谱法测定家兔组织中乌头碱的含量[J]. 2007, 13(7): 56-58.
[86]王朝虹,叶敏,邢俊波,等.高效液相色谱-质谱法测定乌头碱在急性中毒家兔体内的分布[J].色谱, 2005, 23(3): 316-318.
[87]王瑞.附子质量评价及乌头碱类成分药动学研究[D].北京:北京中医药大学, 2007.
[88]张国红,由会玲,刘云肖.乌头生物碱含量测定方法现况[J].河北中医医学报, 2000, 15(1): 45-47.
[89]李路娥,罗群,王跃华.乌头碱检测方法综述[J].成都大学学报(自然科学版) 2005, 24(4): 15-17.
[90]李娅萍,田颂九,王国荣.乌头类药物的化学成分及分析方法概况[J].中国中药杂志, 2001, 26(10): 659-662.
[91]赵永芳.生物化学技术原理及应用[M].北京:科学技术出版社, 2002.
[92]张春水.乌头类双酯型生物碱的检测现状[J].刑事技术, 1998, (3): 11-12.
[93]王慕邹,李百龙,高凤英.乌头中主要生物碱的高效液相色谱测定[J].药学学报, 1983, 18(9): 689-691.
[94]张兴华,王忠军.高效液相色谱法测定家兔血液中乌头碱[J].中国医药工业杂志, 1989, 20(5): 211-213.
[95]杨一先,张兴华,胡炳蔚.体内痕量乌头碱的HPLC的测定[J].中国法医学杂志, 1989, 4(3): 178-180.
[96] Xu W, Hu B W. Postmortem redistribution kinetics of aconitine in rabbits[J]. Xi’AN Med Uinv, 1994, 6(1): 41-45.
[97] Xu W, Hu B W. Study of aconitine degradation kinetics in rabbit corpses[J]. Xi’ANMed Uinv, 1996, 8(1): 22-26.
[98]金鸣,李红海,汪升.高效液相色谱法快速分离测定组织中的乌头碱[J].中国法医学杂志, 2005, 20(4): 215-217.
[99] Wang Z H, Wen J, Xing U B. Quantitative determination of diterpenoid alkaloids in four species of Aconitum by HPLC[J]. Journal of Pharmaceutical and Biomedical Analysis, 2006, 40: 1031-1034.
[100] Xie Y, Jinag Z H, Zhou H. Simultaneous determination of six Aconitum alkaloids in proprietary Chinese medicines by high-performance liquid chromatography[J]. Journal of Chromatography A, 2005, 1093: 195-203.
[101] Feng H T. Determination of five toxic alkaloids in two common herbal medicines with capillary electrophoresis[J]. Journal of Chromatography A, 2002, 973: 243-247.
[102]孙爱民.高效毛细管电泳法测定中草药川乌、草乌中乌头碱的含量[J].色谱, 1999, 17(1): 67-69.
[103] Mizugaki M, Ohyama Y, Kimura K, et al. Analysis of aconitum alkaloids by means of gas chromatography/selected ion monitoring[J]. Eisei Kagaku, 1988, 34: 359-365.
[104]王朝虹,何毅,张继宗.生物检材中乌头碱的GC/MS分析[J].中国法医学杂志, 2003, 18(3): 145-146.
[105] Ohta H, Seto Y, Tsunoda N, et al. Determination of Aconitum alkaloids in blood and urine samples. I. High-performance liquid chromatographic separation, solid-phase extraction and mass spectrometric confirmation[J].J. Chromatogr.B, 1997, 691: 351-356.
[106] Wada K, Bando H, Kawahara N, et al. Determination and Quantitative Analysis of Aconitum Alkaloids in Plants by Liquid Chromatography Atmospheric Pressure Chemical Ionization Mass Spectrometry.[J]. J Chromatogr A, 1993 , 644: 43-48.
[107] Ohta H, Seto Y, Tsunoda N, et al. Determination of Aconitum Alkaloids in Blood and Urine SamplesⅡ. Capillary Liquid Chromatographic-Frit Fast Atom Bombardment Mass Spectrometric analysis.[J]. J Chromatogr B, 1998, 714: 215-221.
[108]王俊伟,郭亚飞,陈丽涛,等.乌头碱的LC-MS定量分析[J].分析测试学报, 2004, 23(增): 57-61.
[109]陈晓红,李小平,姚浔平,等.高效液相色谱-质谱联用同时测定尿液中4种生物碱[J].中国卫生检验杂志, 2006, 16(6): 691-692.
[110]王兆基,何绍基,徐树棋.液相色谱/质谱/质谱联用法测定乌头属药材及中成药中乌头类生物硷含量[J].分析化学, 2001, 29(4): 391-395.
[111]周娣,潘冠民.生物检材中乌头碱、次乌头碱、新乌头碱的LC/MS/MS分析[J].现代科学仪器, 2005(4): 64-67.
[112]张润生,余琛,刘罡,等.血液中乌头碱、次乌头碱、新乌头碱的LC/MS/MS分析[J].中国法医学杂志, 2004, 19(5): 265-267.
[113] Wang Z H, Wang Z P, Wen J, et al. Simultaneous determination of three aconitum alkaloids in urine by LC-MS-MS [J]. Journal of Pharmaceutical and Biomedical Analysis, 2007, 45: 145-148.
[114] Beyer J, Peters F T, Kraemer T, et al. Detection and validated quantification of toxic alkaloids in human blood plasma-comparison of LC-APCI-MS with LC-ESI-MS/MS [J]. Journal of Mass Spectrometry, 2007, 42: 621-633.
[115] Wang Y, Liu Z Q, Song F R, et al. Electrospray ionization tandem mass spectrum- etric study of the aconotines in the roots of aconite[J]. Rapid Commun. Mass Spectrom., 2002, 16: 2075-2086.
[116] Li R, Wu Z J, Zhang F, et al. Differentiation of three pairs of aconite alkaloid isomers from Aconitum nagarum var. lasiandrum by electrospray ionization tandem mass spectrometry[J]. Rapid Commun. Mass Spectrom., 2006, 20: 157-170.
[117]陈兰慧,金莲姬,苏忠民,等.乌头碱类生物碱电喷雾串联质谱行为及碎片离子稳定性的量子化学计算[J].高等学校化学学报, 2005, 26(12): 2340-2344
[118] Exploring the ester-exchange reactions of diesterditerpenoid alkaloids in the aconite decoction process by electrospray ionization tandem mass spectrometry. [J]. Rapid Commun. Mass Spectrom., 2003, 17: 279-284.
[2]史向国.必特螺旋霉素体内代谢与药物动力学研究[D].沈阳:沈阳药科大学, 2003.
[3]王广基.药物代谢动力学[M].北京;化学工业出版社, 2005.
[4]刘睿,谢跃生,潘桂湘,等.药物组织蛋白结合率测定方法的研究进展[J].天津中医药, 2007, 24(6): 526-528
[5] Akimasa S, Nobuko I, Tomoko K, et al. Plasma protein binding study of oxybutynin by high-performance frontal analysis[J]. Journal of Chromatography B, 2002, 768, 1: 177-188 .
[6] Sonu S S. Measurement of drugrotein binding by immobilized human serum albumin-HPLC and comparison with ultrafiltration[J]. Journal of Chromatography B, 2006, 834: 108-116.
[7]周艳钢,李焕德.体内药物代谢研究的意义与应用[J].中南药学, 2009, 17(1): 46-50.
[8]阿基业,王广基.药物代谢研究与药物设计及结构修饰[J].药学进展, 2002, 26(2): 80-86.
[9] Kazmaier S, Hanekop G G, Buher W, et a1. Myocardial consequences of remifentanil in patients with coronary artery disease[J]. J-Anaesth, 2000, 84(5): 578-583.
[10]王淑月,尹宏军,陈竞洪.软药原理与新药设计[J].河北工业科技, 2004, 21(1):58-60.
[11] Bodor N, Buchwald P. Soft drug design: general principles and recent applications[J]. Med Res Rev, 2000, 20(1): 58-101.
[12] Baillie T A. Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism [J].Chem Res Toxicol, 2008, 21(1): 129-137.
[13] Naito S, Furuta S, Yoshida T, et al. Current opinion: Safety evaluation of drug metabolites in development of pharmaceuticals[J]. J Toxicol Sci, 2007, 32(4): 329-341.
[14]王爱国.国内外药物不良反应监测发展概况[J].中国临床药理学杂志, 2009, 25(1): 75-77.
[15] Henz B M. The pharmacologic profile of desloratadine: a review[J]. Allergy, 2001,56(Suppl): 7-13.
[16]马道铭,徐文严.抗组胺新药--盐酸非索那定[J].国外医学皮-肤性病学分册, 1999, 25(3): 129-131.
[17]柴士伟,潘桂湘.药物代谢研究方法简述[J].天津中医药, 2006, 23, (1): 83-85.
[18]谈恒山,张海霞,方芸,等.近10年国内药物体外代谢研究进展[J].江苏药学与临床研究, 2006, 14(5): 297-300.
[19]王佳.药物体外肝代谢研究方法[J].代百东亚太传统医药, 2008, 4(3): 48-50.
[20]郑维思,陈一岳.体外肝代谢系统的研究与应用[J].广东药学院学报, 2007, 23(2): 225-228.
[21]韩聚强,刘树贤.体外肝细胞培养技术新进展[J].河北医科大学学报, 2002, 23(3): 185-187.
[22]邹文,周文.药物代谢的种属和性别差异研究[J].齐鲁药事, 2007, 26(12): 735-737.
[23]王羽,柳晓泉,王广基.药物的肝外代谢[J].药学进展, 2004, 28(7): 289-294.
[24] Ayrton A, Morgan P. Role of transport proteins in drug absorption, distribution and excretion[J]. Xenobiotica, 2001, 31(8-9): 469-497.
[25] Lin J, Yao L, Lame M, et al. The increased emphasis of ADME properties in hit-to-lead drug discovery[J]. Acta Pharmacol Sin, 2006, 27(suppl 1): 226-229.
[26] Obach R S, Baxter J Q, Liston T E, et al. The predietion of human phannacokineic parameters from preclinical and in vitro metabolism data[J]. J.Pharmacol.Exp.Ther, 1997, 283: 46-58 .
[27]胡灵,陈汇.药物代谢动力学在药物研究中的应用与进展(上)[J].中国药师, 2006, 8(5): 651-653.
[28]胡灵,陈汇.药物代谢动力学在药物研究中的应用与进展(上)[J].中国药师, 2007, 10(7): 654-658.
[29]裴利霞,杜冠华.药物代谢动力学研究进展[J].中国医药导刊, 2006, 8(5): 328-329.
[30]索晴,刘树民.近年来中药在肠内的吸收代谢研究方法与思路概述[J].中国中医药科技, 2007, 14(2): 141-142.
[31]董红林,蔡军伟,杨晶.研究小肠吸收的常用方法医医学医学[J].医学研究通讯, 1999, 28(12): 28-29.
[32]李高,方超.药物肠道吸收的生物学研究方法[J].中国药学杂志, 2002, 37, (10):726-729.
[33]水文波.中药活性成分的小肠吸收研究[D].杭州:浙江大学药学院药物信息学研究所, 2006.
[34]程锦,狄留庆.在体肠段灌流模型在中药吸收研究中的应用[J].中国中医药信息杂志, 2008, 15(2): 98-100.
[35]中华人民共和国卫生部药政管理局.现代实用本草(上册)[M].北京:人民卫生出版社, 1997.
[36]中国药品生物制品检验所.中国民族药志[M].北京:人民卫生出版社, 1990.
[37]国家中医药管理局.中华草本(第3册)[M].上海:上海科学技术出版社, 1999.
[38]汪沪双.乌头碱抗风湿作用的药效学研究概述[J].基层中药杂志, 1996, 10, (3): 45-46.
[39]杨姝,金振辉,羊晓东,等.乌头属植物的化学成分及药理作用研究进展[J].云南农业大学学报, 2007, 22(12): 293-295.
[40]蒙其淼,梁洁,吴桂凡,等.生物碱类化合物药理作用研究进展[J].时珍国医国药, 2003, 14 (11): 700-702.
[41]王文祥.现代中药药理学[M].天津:天津科学技术出版社, 1997.
[42]沈映君.中药药理学[M].北京:人民卫生出版社, 2000.
[43]王雅贤,贾宽,张德山,等.乌头碱对小鼠免疫功能影响的实验研究[J].中医药信息, 1989, 5(5): 40-42.
[44]宋东江,陆满文,彭建中.乌头碱类化合物抗炎作用研究进展[J].中草药, 1990, 21(11): 43-45.
[45]林凌云,陈巧鸿,王锋鹏.去甲二萜生物碱的药理活性[J].华西药学杂志, 2004, 19(3): 200-205.
[46]唐希灿,冯洁. 3-乙酰乌头碱氢溴酸盐的镇痛和局部麻醉作用[J].中国药理学报, 1981, 2(1): 82-84.
[47]周远鹏,刘文化,曾贵云.乌头碱及其类似物的毒性和对心脏收缩功能的影响[J].药学学报, 1984, 19(9): 641-646.
[48]周远鹏.附子及其主要成分的药理作用和毒性[J].药学学报, 1983, 18(5): 394-400.
[49]张为亮,徐楚江,杨明,等.附子毒效关系的实验研究[J].广西中医药, 1997,20(3): 43-44.
[50] Yunusov M S. Diterpenoid alkaloids[J]. Nat Prod Rep 1993, 10(5): 471-486.
[51]王锋鹏.乌头属和翠雀属植物中生物碱化学研究概况[J].药学学报, 1981, 16(12): 943-959.
[52]梁笑天.我国二萜生物碱化学的最近进展[J].有机化学, 1986, 5: 335-340.
[53] Pelletier S W, Page S W. Diterpenoid alkaloids[J]. Nat Prod Rep, 1984, 1: 375-381.
[54]彭波,杨华元.乌头、附子及其主要生物碱研究进展[J].华西药学杂志, 1993, 8(3): 158-161.
[55]萧培根,王文采.中国毛茛科药用植物的研究Ⅱ.乌头属的药用植物[J].药学学报, 1965, 12(10): 683-703.
[56]符华林.我国乌头属药用植物的研究概况[J].中药材, 2004, 27(2): 149-152.
[57]肖培根,王锋鹏,高峰,等.中国乌头属植物药用亲缘学研究[J].植物分类学报, 2006, 44(1) 1-46.
[58]李娅萍,田颂九,王国荣.乌头类药物的化学成分及分析方法概况[J].中国中药杂志, 2001, 26(10): 659-662.
[59]陈信义,李峨,侯丽,等.乌头类双酯型生物碱研究进展与应用前景评述[J].中国中医药信息杂志, 2004, 11(10): 922-923.
[60]高黎明,郑尚珍,沈序维,等.乌头属植物中二萜生物碱研究进[J].西北师范大学学报, 1999, 35(2): 109-116.
[61]高黎明,毛学峰,魏小梅,等.二萜类生物碱的药理作用及构效关系研究概况[ J ].西北师范大学学报, 1999, 35(1): 98-103.
[62]张宏贵,史向国,孙莹,等.兔血液中乌头碱代谢产物的研究[J].吉林大学学报(理学版), 2006, 44(2): 284-286.
[63]张宏贵.毒性乌头生物碱代谢产物研究[D].长春:吉林大学药学院, 2006.
[64] Zhang H G, Shi X G S, Sun Y, et al. New Metabolites of Aconitine in Rabbit Urine Chinese Chemical Letters[J]. 2002, 13(8): 758-760.
[65]张宏贵,滕坤,刘永刚,等. LC-MSn分析新乌头碱在兔尿液中的代谢产物[J].中国法医学杂志, 2007, 22(6): 401-402.
[66] Zhang H G, Sun Y, Duan M Y, et al. Separation and identification of Aconitum alkaloids and their metabolites in human urine[J]. Toxicon, 2005, 46: 500-506.
[67] Xie F M, Wang H C, Shu H L, et al. Separation and characterization of the metabolicproducts of lappaconitine in rat urine by high-performance liquid chromatography[J]. Journal of Chromatography BiomedicalApplications, 1990, 526: 109-112.
[68] Yoshioka N, Gonmori K, Tagashira A, et al. A case of aconitine poisoning with analysis of aconitine alkaloids by GC/SIM [J]. ForensicScience International, 1996, 81: 117-120.
[69]孙莹,张宏桂,史向国,等.兔体内乌头碱代谢产物研究[J].药学学报, 2002, 37(10): 781-783.
[70]孙莹,张群书,董丽丹,等.乌头属中药中主要生物碱在不同性别家兔尿中的代谢产物[J].吉林大学学报(理学版), 2007, 45(6): 1032-1034.
[71]王朝虹,文静,陈义华,等.液相色谱质谱联用测定乌头碱在家兔体内代谢产物中国法医学杂志[J], 2006, 21(2): 88-90.
[72]艾路,孙莹,张宏桂.复方中药中乌头生物碱在人体内的代谢产物[J].北京中医药大学学报. 2007, 30(6): 417-422.
[73]李文东.乌头碱体内代谢产物分析方法研究[D].北京:中国医科科学院和北京协和医科大学, 2001.
[74] Wang Y G, Wang S Q , Liu Y X, et al. Characterization of metabolites and cytochrome P450 isoforms involved in the microsomal metabolism of aconitine[J]. Journal of Chromatography B, 2006, 844: 292-300.
[75]赵宇峰,宋凤瑞,国新华,等.利用软电离质谱技术研究乌头碱在肠内细菌中的生物转化[J].高等学校化学学报, 2008, 29(1): 55-59.
[76]赵宇峰,宋凤瑞,越皓,等. 16-O-去甲基去氧乌头碱在肠内细菌中的生物转化研究[J].分析化学, 2007, 35(12): 1711-1715.
[77]赵宇峰,宋凤瑞,王曦烨,等. 16-O-去甲基乌头碱的生物转化及电喷雾质谱研究[J].化学学报, 2008, 66(5): 525-530.
[78]赵宇峰,宋凤瑞,越皓,等.乌头碱的代谢产物去氧乌头碱的生物转化及其电喷雾串联质谱[J]. 2007, 28(11): 2051-2055.
[79] Kentaro W, Makoto N, Hideyuki H, et al. Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice[J]. Forensic Science International, 2005, 148: 21-29.
[80]李锐,晏亦林,周莉玲,等.四逆汤的药动学研究[J].中成药, 2002, 24(10): 777-780.
[81]晏亦林.四逆汤有效部位的药代动力学-药效动力学研究[D].广州:广州中医药大学, 2001.
[82]肖凤霞,周莉玲,李锐,等.血药浓度法测定四逆汤制剂中乌头生物碱的药动学参数[J].广州中医药大学学报, 2001, 18(3): 243-246.
[83]王朝虹,文蛟,何毅.液相色谱-质谱联用测定乌头碱血药浓度及其药代动力学参数的方法学研究[J].分析测试学报, 2004, 23(增): 51-54.
[84]李文东,马辰.口服制川乌提取物后家兔体内乌头类双酯型生物碱的组织分布[J].药学学报, 2005, 40(6): 539 -543.
[85]李文东,马辰.高效液相色谱法测定家兔组织中乌头碱的含量[J]. 2007, 13(7): 56-58.
[86]王朝虹,叶敏,邢俊波,等.高效液相色谱-质谱法测定乌头碱在急性中毒家兔体内的分布[J].色谱, 2005, 23(3): 316-318.
[87]王瑞.附子质量评价及乌头碱类成分药动学研究[D].北京:北京中医药大学, 2007.
[88]张国红,由会玲,刘云肖.乌头生物碱含量测定方法现况[J].河北中医医学报, 2000, 15(1): 45-47.
[89]李路娥,罗群,王跃华.乌头碱检测方法综述[J].成都大学学报(自然科学版) 2005, 24(4): 15-17.
[90]李娅萍,田颂九,王国荣.乌头类药物的化学成分及分析方法概况[J].中国中药杂志, 2001, 26(10): 659-662.
[91]赵永芳.生物化学技术原理及应用[M].北京:科学技术出版社, 2002.
[92]张春水.乌头类双酯型生物碱的检测现状[J].刑事技术, 1998, (3): 11-12.
[93]王慕邹,李百龙,高凤英.乌头中主要生物碱的高效液相色谱测定[J].药学学报, 1983, 18(9): 689-691.
[94]张兴华,王忠军.高效液相色谱法测定家兔血液中乌头碱[J].中国医药工业杂志, 1989, 20(5): 211-213.
[95]杨一先,张兴华,胡炳蔚.体内痕量乌头碱的HPLC的测定[J].中国法医学杂志, 1989, 4(3): 178-180.
[96] Xu W, Hu B W. Postmortem redistribution kinetics of aconitine in rabbits[J]. Xi’AN Med Uinv, 1994, 6(1): 41-45.
[97] Xu W, Hu B W. Study of aconitine degradation kinetics in rabbit corpses[J]. Xi’ANMed Uinv, 1996, 8(1): 22-26.
[98]金鸣,李红海,汪升.高效液相色谱法快速分离测定组织中的乌头碱[J].中国法医学杂志, 2005, 20(4): 215-217.
[99] Wang Z H, Wen J, Xing U B. Quantitative determination of diterpenoid alkaloids in four species of Aconitum by HPLC[J]. Journal of Pharmaceutical and Biomedical Analysis, 2006, 40: 1031-1034.
[100] Xie Y, Jinag Z H, Zhou H. Simultaneous determination of six Aconitum alkaloids in proprietary Chinese medicines by high-performance liquid chromatography[J]. Journal of Chromatography A, 2005, 1093: 195-203.
[101] Feng H T. Determination of five toxic alkaloids in two common herbal medicines with capillary electrophoresis[J]. Journal of Chromatography A, 2002, 973: 243-247.
[102]孙爱民.高效毛细管电泳法测定中草药川乌、草乌中乌头碱的含量[J].色谱, 1999, 17(1): 67-69.
[103] Mizugaki M, Ohyama Y, Kimura K, et al. Analysis of aconitum alkaloids by means of gas chromatography/selected ion monitoring[J]. Eisei Kagaku, 1988, 34: 359-365.
[104]王朝虹,何毅,张继宗.生物检材中乌头碱的GC/MS分析[J].中国法医学杂志, 2003, 18(3): 145-146.
[105] Ohta H, Seto Y, Tsunoda N, et al. Determination of Aconitum alkaloids in blood and urine samples. I. High-performance liquid chromatographic separation, solid-phase extraction and mass spectrometric confirmation[J].J. Chromatogr.B, 1997, 691: 351-356.
[106] Wada K, Bando H, Kawahara N, et al. Determination and Quantitative Analysis of Aconitum Alkaloids in Plants by Liquid Chromatography Atmospheric Pressure Chemical Ionization Mass Spectrometry.[J]. J Chromatogr A, 1993 , 644: 43-48.
[107] Ohta H, Seto Y, Tsunoda N, et al. Determination of Aconitum Alkaloids in Blood and Urine SamplesⅡ. Capillary Liquid Chromatographic-Frit Fast Atom Bombardment Mass Spectrometric analysis.[J]. J Chromatogr B, 1998, 714: 215-221.
[108]王俊伟,郭亚飞,陈丽涛,等.乌头碱的LC-MS定量分析[J].分析测试学报, 2004, 23(增): 57-61.
[109]陈晓红,李小平,姚浔平,等.高效液相色谱-质谱联用同时测定尿液中4种生物碱[J].中国卫生检验杂志, 2006, 16(6): 691-692.
[110]王兆基,何绍基,徐树棋.液相色谱/质谱/质谱联用法测定乌头属药材及中成药中乌头类生物硷含量[J].分析化学, 2001, 29(4): 391-395.
[111]周娣,潘冠民.生物检材中乌头碱、次乌头碱、新乌头碱的LC/MS/MS分析[J].现代科学仪器, 2005(4): 64-67.
[112]张润生,余琛,刘罡,等.血液中乌头碱、次乌头碱、新乌头碱的LC/MS/MS分析[J].中国法医学杂志, 2004, 19(5): 265-267.
[113] Wang Z H, Wang Z P, Wen J, et al. Simultaneous determination of three aconitum alkaloids in urine by LC-MS-MS [J]. Journal of Pharmaceutical and Biomedical Analysis, 2007, 45: 145-148.
[114] Beyer J, Peters F T, Kraemer T, et al. Detection and validated quantification of toxic alkaloids in human blood plasma-comparison of LC-APCI-MS with LC-ESI-MS/MS [J]. Journal of Mass Spectrometry, 2007, 42: 621-633.
[115] Wang Y, Liu Z Q, Song F R, et al. Electrospray ionization tandem mass spectrum- etric study of the aconotines in the roots of aconite[J]. Rapid Commun. Mass Spectrom., 2002, 16: 2075-2086.
[116] Li R, Wu Z J, Zhang F, et al. Differentiation of three pairs of aconite alkaloid isomers from Aconitum nagarum var. lasiandrum by electrospray ionization tandem mass spectrometry[J]. Rapid Commun. Mass Spectrom., 2006, 20: 157-170.
[117]陈兰慧,金莲姬,苏忠民,等.乌头碱类生物碱电喷雾串联质谱行为及碎片离子稳定性的量子化学计算[J].高等学校化学学报, 2005, 26(12): 2340-2344
[118] Exploring the ester-exchange reactions of diesterditerpenoid alkaloids in the aconite decoction process by electrospray ionization tandem mass spectrometry. [J]. Rapid Commun. Mass Spectrom., 2003, 17: 279-284.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |