延胡索乙素手性药代动力学及元胡白芷配伍影响研究
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摘要
本文以纯天然止痛验方元胡白芷方中的延胡索乙素消旋体为主要研究对象,以手性固定相-HPLC为主要监测手段,在四氢原小檗碱同类物对映体拆分研究和延胡索乙素对映体体内定量分析方法建立的基础上,首次研究并揭示了延胡索乙素对映体在大鼠生物体液中的立体选择性药代动力学特征;首次研究了延胡索乙素对映体在作用部位脑部不同区域的作用浓度以及经时动态变化,从药代动力学的角度定量地阐明延胡索乙素脑部作用位点药效强度变化的内涵;探讨元胡白芷配伍对延胡索乙素手性特征的影响,提示元胡伍用白芷后具协同增效作用,从药动学的角度证实了方剂配伍的合理性。研究成果可为延胡索乙素及四氢原小檗碱同类物的深入研究以及中药复方配伍规律研究等提供一定的理论基础和技术支持。
Tetrahydropalmatine (dl-THP) is a biologically active ingredient in a Chinese herb prescription named Yuanhu-Baizhi. This paper has focused on the enantiomeric separation and chiral pharmacokinetics of THP in animals, using a chiral HPLC method coupled with achiral column. The stereo selective disposition kinetics, such as plasma pharmacokinetics and excretion, of THP enantiomers in rats after an oral dose of the racemate was revealed for the first time. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured and the striatum displayed significantly higher concentrations. The effects of the ingredients in Yuanhu-Baizhi prescription on the pharmacokinetics of THP enantiomers were also studied. The results of this thesis provided theoretical basis and techniques for further studies on tetrahydroprotoberberines. It was suggested that the pharmacokinetics of Chinese medicines could be used as an effective way of seeking inherent law of complex prescription principle.
Tetrahydropalmatine (dl-THP) is a biologically active ingredient in a Chinese herb prescription named Yuanhu-Baizhi. This paper has focused on the enantiomeric separation and chiral pharmacokinetics of THP in animals, using a chiral HPLC method coupled with achiral column. The stereo selective disposition kinetics, such as plasma pharmacokinetics and excretion, of THP enantiomers in rats after an oral dose of the racemate was revealed for the first time. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured and the striatum displayed significantly higher concentrations. The effects of the ingredients in Yuanhu-Baizhi prescription on the pharmacokinetics of THP enantiomers were also studied. The results of this thesis provided theoretical basis and techniques for further studies on tetrahydroprotoberberines. It was suggested that the pharmacokinetics of Chinese medicines could be used as an effective way of seeking inherent law of complex prescription principle.
引文
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39.张壮,闫彦芳,陈可冀.中国中药杂志,2000,25(11):688.
40.项琪,程刚,陈济民.中国药学杂志,2000,35(9):615.
41.国家药典委员会 编著 中华人民共和国药典 (2000版,Ⅰ部),北京:化学工业出版社,2000,pp216.
2. Ariens EJ. Pharmacol Sci, 1993, 14: 68
3. Hutt AJ, Tan SC. Drugs 1996, 52: 1.
4. Nation RL. Clin Pharmacokinet 1994, 27: 249.
5. Tucker GT, Lennard MS. Pharmacol Ther 1990, 45: 309.
6. Caldwell J. J Chromatogr A 1996, 719: 3.
7. Jamal F, Mehvar R, Pasutto FM. J Pharm Sci, 1989, 78: 695.
8. Wade DN, Mearriek TP, Morris JL. Nature, 1973, 242: 463.
9. Ahrned S, Imai T, Otagiri M. Enantiomer, 1997, 2: 151.
10. Paliwl JK, Smith DE, Cox SR, et al. J Pharmacokinetic Biopharm, 1993, 21: 145.
11. Kroemer HK, Fromn MF, Buhl K, et al. Circulation, 1994, 89: 2396.
12. Takahashi H, Eehizen H. Clin Pharmacokinet, 2001, 40: 587.
13. Kaminsky LS, Zhang ZY. Pharmacol Ther, 1997, 73(1): 67.
14. Campbell DB. Eur J Drug Metab Pharmacokinet 1990, 15: 109.
15. Evans AM, Nation RH, Sansom LN, Vochner F, Somogyi AA. Br J Clin Pharmacol 1988, 26: 771.
16.何煦昌.中国医药王业杂志,1997,28(11):519.
17.严淋,严拯宇,黎红梅.邯郸医学高等专科学校学报,2001,14(4):303.
18.王亚芹,钟大放,陈仁弟.药学学报,1998,32(2):138.
19.陈冰,蔡卫民,万伟.中国药学杂志,1998,33(9):546.
20. Rhatti MM, Foster RT. J Chromatogr., 1992, 579(2): 361.
21. Ssllustio BC, Abas A, Hayball PJ, et al. JChromatogr., 1986, 374(2): 329.
22.谢剑炜,杨造萍,阮金秀.药学学报.1998:33(2):141
23.彭清涛,胡文祥,谭生键.药学学报,1998,33(10):793
24. SO Choi, SH Lee, HS Kong, EJ Kim, HY P Choo. J Chromatogr B, 2000, 744: 201.
25. Miguel AC, Emilio GQ, Belen S, Jose R A. J Chromatogr A, 2004, 1031: 219.
26. S. A. Corlett and H. Chrystyn. J Chromatogr B, 1994, 654: 152
27. C. Cristofol, G. Virkel, L. Alvarez, M. Arboix and C. E. Lanusse. M. Biopharmaceutics & Drug Disposition, 2000, 21: 303.
28. SC Wang, LC He, F Liu. Acta Pharmaceutica Sinica, 2001, 36: 364.
29.向大雄,李焕德,胥新元.中国实验方剂学杂志.2002,8(1):61.
30.吴民淑,王广基,蔡晓辉,等.药学学报,2002,37(7):551.
31. Tung-Hu Tsai, Chien-Cheng Liang. Int J Pharmaceutics, 2001, 216: 61.
32.肖凤霞,周莉玲,李锐,等.广州中医药大学学报,2001,18(3):243.
33. Hsiu SL, Huang TY, Hou YC, et al. Life Sci, 2002, 70(13): 1481.
34.洪馨,宓穗卿,王宁生.中药新药与临床药理,2000,11(5):286.
35.邹节明,孟杰,颜正化,等.中草药,2002,33(1):55.
36.庞志功,汪宝琪,李海峰.西安医科大学学报,2001,22(4):319.
37.胡大裕,朱景申,常明向.同济医科大学学报,2001,30(4):384.
38.黄熙,任平,陈可冀,等.中国中西医结合杂志,2001,21(1):7.
39.张壮,闫彦芳,陈可冀.中国中药杂志,2000,25(11):688.
40.项琪,程刚,陈济民.中国药学杂志,2000,35(9):615.
41.国家药典委员会 编著 中华人民共和国药典 (2000版,Ⅰ部),北京:化学工业出版社,2000,pp216.