吴茱萸碱、吴茱萸次碱和左旋四氢巴马亭在微生物和大鼠体内的代谢研究
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摘要
吴茱萸(Evodia rutaecarpa Juss.Benth.)为著名中药复方吴茱萸汤中的君药，主要含生物碱类活性化合物，具有明显的温胃、止呕之功效。吴茱萸碱和吴茱萸次碱作为吴茱萸中最重要的两种生物碱，发现具有强心、抗炎、镇痛和抗肿瘤活性，因此引起了国内外的广泛关注。左旋四氢巴马亭为防己科植物华千金藤(Stephania ainica Diels)块根中提取出的一种生物碱，为延胡索(Corydalis yanhusuo W.T.Wang)中延胡索乙素的左旋体，中药制剂颅痛定中的主要成分，具有较强的镇痛作用。为了发现活性更强、副作用更小的活性化合物和鉴定其微量的体内代谢产物，人们一直在寻找有效的方法对这类化合物进行结构修饰和改造。
对于药物的安全性和有效性评价中重要研究内容之一就是了解药物在体内的代谢过程。微生物转化方法已经成为天然产物结构修饰和体内代谢研究的重要手段之一，因其反应具有显著的位置选择性和立体选择性，可以催化生成自然界或化学界难以获得的，结构新颖的天然产物衍生物，同时也因其具有与人类类似的代谢酶等特点，被用来模拟药物在体内的代谢行为，并从中分离和鉴定人类或动物体内微量或痕量的代谢产物。
为了探讨吴茱萸温胃、止呕作用的药效物质基础，并系统研究吴茱萸碱和吴茱萸次碱在微生物与大鼠体内的代谢，本论文对吴茱萸中不同提取部位进行了化学和药理学的初步研究，并采用LC／MS／MS与现代光谱技术对吴茱萸碱和吴茱萸次碱的微生物转化与体内代谢进行了深入系统的研究。同时，对左旋四氢巴马亭的体内外的代谢产物和代谢途径也进行了深入探讨。
建立了HPLC方法测定吴茱萸中吴茱萸碱、吴茱萸次碱、吴茱萸苦素和柠檬苦素的含量。其中4个成分的平均含量分别为0.71％、0.72％、0.43％和0.57％。考察了吴茱萸中不同组分对大鼠离体胃底平滑肌条运动和对醋酸所致小鼠扭体的影响，吴茱萸的总提物(a)、吴茱萸中的总生物碱(d)和水溶性部分(e)对Ach刺激的大鼠胃条痉挛性收缩活动的影响与空白组比较具有非常显著性差异(P＜0.01)。除挥发油部分(b)外，其余提取部位对醋酸所致小鼠扭体的镇痛作用与空白组比较均具有非常显著性差异(P＜0.01)。
系统研究了吴茱萸碱和吴茱萸次碱的微生物转化。通对20余株微生物进行转化筛选，结果表明Mucor，Cunninghamella和Penicillium等属的菌株对以上两种生物碱的转化作用较好。在筛选结果的基础上，选取微紫青霉Penicillium janthinellum AS 3.510和短刺小克银汉霉Cunninghamelal blakesleana AS 3.970分别对吴茱萸碱和吴茱萸次碱进行了放大生物转化试验。共分离得到8个产物，通过柱层析和半制备HPLC分离，其结构光谱鉴定为：10-羟基吴茱萸碱(J-3-1)、11-羟基吴茱萸碱(J-1)、3-羟基吴茱萸碱(J-3-2)、对羟基苯甲醇(J-2-1)、对羟基苯乙醇(J-2-2)、10-羟基吴茱次萸碱(C-1)、3-羟基吴茱萸次碱(C-2)和3，10-二羟基吴茱萸次碱(C-6)，其中除J-2-1和J-2-2外均为新化合物。转化反应的动态考察表明，Penicillium janthinellum AS 3.510和Cunninghamella blakesleana AS 3.970可以在7日内分别将底物转化成为羟基化代谢产物，但转化率比较低。采用MTT方法对吴茱萸碱和吴茱萸次碱的转化产物进行了体外细胞毒活性测试，结果表明J-1、J-3-1、J-3-2、C-2和C-6对BGC-823、Bel-7402、MCF-7和HL-60四个肿瘤细胞株均具有不同程度的细胞毒活性，其中J-1对各细胞株的活性均强于底物吴茱萸碱。
考察了20余株微生物菌株对左旋四氢巴马亭的微生物转化，选用转化能力最强的微紫青霉Penicillium janthinellum AS 3.510对其进行放大转化研究。共分离得到3个转化产物，分别为左旋紫堇单酚碱(T-1，1-corydalmine)、3-去甲基左旋四氢巴马亭(T-2，1-corypalmine)和9-去甲基左旋四氢巴马亭(T-3)。转化反应的动态考察表明，Penicillium janthinellum AS 3.510能够缓慢催化O-去甲基化反应，7日后转化反应仍持续进行。
采用LC／MS／MS方法，并结合微生物转化获得的单体对照品，系统研究了吴茱萸碱、吴茱萸次碱和左旋四氢巴马亭在大鼠体内的代谢产物和代谢途径。分别鉴定了2个吴茱萸碱在大鼠尿液和粪便中的代谢产物(J-3-1和J-3-2)和3个左旋四氢巴马亭在大鼠粪便中的代谢产物(T-1，T-1和Y-3)，并初步推测了3个左旋四氢巴马亭在大鼠粪便中的代谢产物的结构。并对此3个生物碱在微生物与及大鼠体内的代谢途径和代谢产物进行了对比。
Evodia rutaecarpa Juss. Benth is the most important component of famous Wu-Zhu-Yu decoction of China. Previous studies showed that Evodia is effective in the treatment of stomach diseases. Evodiamine and rutaecarpine are the two major active indole alkaloids in the title plant. In recent years, they have been found to exhibit cardiotonic, anti-inflammation and antitumor activities and received more and more attention from scientists of various fields. 1-Tetrahydropalmatine (1-THP), a naturally occurring neuroactive alkaloid from Stephania ainiaca Diels, has been widely used as analgetic medicine-Lu Tong Ding in China for many years. To find more effective compounds with low toxicity or to identify the in vivo metabolites, scientists have been searching for the approach to modify the structures by efficient methods.An important factor in the evaluation of safety and efficacy of any drug is the knowledge of how the drug is metabolized. Microbial metabolic studies have such advantages over chemical synthesis as high stereo- and regio-selectivity and are becoming a complementary tool in the study of drug metabolism in mammals for the reason that most families of human liver cytochrome P450 have been expressed in microorganisms as individual enzymes. For obtaining sizable amount of metabolites for pharmacological and toxicological studies, microbial metabolism is clearly useful.In efforts to study the chemical constituents responsible for antiemetic activity of Evodia and the metabolisms in microbial organism and rats of evodiamine and rutaecarpine, the chemical, pharmacological and metabolic studies were carried out. Metabolism of 1-THP in microbial organisms and rats were investigated at the same time.Two HPLC methods were set up to determinate the concentrations of evodiamine, rutaecarpine, rutaevine and evodin in Evodia, respectively, which get the results of 0.71%, 0.72%, 0.57% and 0.43%. Effects on stomach strips of different fractions of Evodia were evaluated. Fractions a, d and e showed obvious activity of antagoning contraction to stomach. Analgesic effect of different fractions of Evodia was also invesgated using acetic-acid induced twitching in mice and its analgesic potency was compared with ibuprofen. The fractions a, c, d and e all showed potential analgesic effect.
Microbial transformations of evodiamine and rutaecarpine were carried out. Twenty strains of fungi were screened for their capabilities to transform the above two alkaloids. It was found that Mucor, Cunninghamella and Penicilliurn species could metabolize evodiamine and rutaecarpine to produce versatile products. Penicilliumjanthinellum AS 3.510 and Cunningharnella blakesleana AS 3.970 were found to be the most potent strain for evodiamine and rutaecarpine and were selected for the preparative-scale biotransformation. Eight products were isolated from the culture supernatant by silica gel column chromatography and preparative RP-HPLC. By means of extensive spectroscopic techniques, their structures were identified as 10-hydroxyevodiamine (J-3-1), 11- hydroxyevodiamine (J-1), 3-hydroxyevodiamine (J-3-2), p-hydroxybenzyl alcohol (J-2-1), p-hydroxyphenylethyl alcohol (J-2-2), 10-hydroxyrutaecarpine (C-1), 3-hydroxyrutaecarpine (C-2) and 3,10-dihydroxyrutaecarpine (C-6), respectively, among which products J-3-1, J-3-2, J-1, C-1, C-2 and C-6 are new compounds. Two substrates were converted into hydroxyl metabolites in 7 days of incubation with low efficiency and the possible biotransforrnation pathways are proposed to account for the formation of the observed products. The in vitro cytotoxicities of the biotransformed products were determined by MTT method. J-1, J-3-1, J-3-2, C-2 and C-6 were found to exhibit potent inhibitory activities against human cancer cell lines (BGC-823, Bel-7402, MCF-7 and HL-60), in which J-1 showed stronger inhibitory activities against four cell lines than evodiamine.
A similar biotransformation process for 1-THP was carried out. Penicillium janthinellum AS 3.510 was selected as the strain for the preparative-scale biotransformation and 3 products were isolated. Their structures were identified as 1-corydalmine (T-1), 1-corypalmine (T-2) and 9-demethyl-1-THP (T-3), respectively. Time-course investigation revealed that Penicillium janthinellum AS 3.510 could slowly demethylate 1-THP at different -OCH_3 positions.
LC/MS/MS analysis was used in the metabolism studies of evodiamine, rutaecarpine and 1-THP in rats. The structures of two metabolites (J-3-1 and J-3-2) of evodiamine and three metabolites of 1-THP (T-1, T-1 and T-3) in rat urine and feces were identified with the reference standards separated from biotransformation. Structures of three metabolites of 1-THP in rat feces were tentative deduced by MS and MS/MS analysis. The metabolisms of ebodiamine, rutaecarpine and 1-THP in microbial organisms and rats were compared.
对于药物的安全性和有效性评价中重要研究内容之一就是了解药物在体内的代谢过程。微生物转化方法已经成为天然产物结构修饰和体内代谢研究的重要手段之一，因其反应具有显著的位置选择性和立体选择性，可以催化生成自然界或化学界难以获得的，结构新颖的天然产物衍生物，同时也因其具有与人类类似的代谢酶等特点，被用来模拟药物在体内的代谢行为，并从中分离和鉴定人类或动物体内微量或痕量的代谢产物。
为了探讨吴茱萸温胃、止呕作用的药效物质基础，并系统研究吴茱萸碱和吴茱萸次碱在微生物与大鼠体内的代谢，本论文对吴茱萸中不同提取部位进行了化学和药理学的初步研究，并采用LC／MS／MS与现代光谱技术对吴茱萸碱和吴茱萸次碱的微生物转化与体内代谢进行了深入系统的研究。同时，对左旋四氢巴马亭的体内外的代谢产物和代谢途径也进行了深入探讨。
建立了HPLC方法测定吴茱萸中吴茱萸碱、吴茱萸次碱、吴茱萸苦素和柠檬苦素的含量。其中4个成分的平均含量分别为0.71％、0.72％、0.43％和0.57％。考察了吴茱萸中不同组分对大鼠离体胃底平滑肌条运动和对醋酸所致小鼠扭体的影响，吴茱萸的总提物(a)、吴茱萸中的总生物碱(d)和水溶性部分(e)对Ach刺激的大鼠胃条痉挛性收缩活动的影响与空白组比较具有非常显著性差异(P＜0.01)。除挥发油部分(b)外，其余提取部位对醋酸所致小鼠扭体的镇痛作用与空白组比较均具有非常显著性差异(P＜0.01)。
系统研究了吴茱萸碱和吴茱萸次碱的微生物转化。通对20余株微生物进行转化筛选，结果表明Mucor，Cunninghamella和Penicillium等属的菌株对以上两种生物碱的转化作用较好。在筛选结果的基础上，选取微紫青霉Penicillium janthinellum AS 3.510和短刺小克银汉霉Cunninghamelal blakesleana AS 3.970分别对吴茱萸碱和吴茱萸次碱进行了放大生物转化试验。共分离得到8个产物，通过柱层析和半制备HPLC分离，其结构光谱鉴定为：10-羟基吴茱萸碱(J-3-1)、11-羟基吴茱萸碱(J-1)、3-羟基吴茱萸碱(J-3-2)、对羟基苯甲醇(J-2-1)、对羟基苯乙醇(J-2-2)、10-羟基吴茱次萸碱(C-1)、3-羟基吴茱萸次碱(C-2)和3，10-二羟基吴茱萸次碱(C-6)，其中除J-2-1和J-2-2外均为新化合物。转化反应的动态考察表明，Penicillium janthinellum AS 3.510和Cunninghamella blakesleana AS 3.970可以在7日内分别将底物转化成为羟基化代谢产物，但转化率比较低。采用MTT方法对吴茱萸碱和吴茱萸次碱的转化产物进行了体外细胞毒活性测试，结果表明J-1、J-3-1、J-3-2、C-2和C-6对BGC-823、Bel-7402、MCF-7和HL-60四个肿瘤细胞株均具有不同程度的细胞毒活性，其中J-1对各细胞株的活性均强于底物吴茱萸碱。
考察了20余株微生物菌株对左旋四氢巴马亭的微生物转化，选用转化能力最强的微紫青霉Penicillium janthinellum AS 3.510对其进行放大转化研究。共分离得到3个转化产物，分别为左旋紫堇单酚碱(T-1，1-corydalmine)、3-去甲基左旋四氢巴马亭(T-2，1-corypalmine)和9-去甲基左旋四氢巴马亭(T-3)。转化反应的动态考察表明，Penicillium janthinellum AS 3.510能够缓慢催化O-去甲基化反应，7日后转化反应仍持续进行。
采用LC／MS／MS方法，并结合微生物转化获得的单体对照品，系统研究了吴茱萸碱、吴茱萸次碱和左旋四氢巴马亭在大鼠体内的代谢产物和代谢途径。分别鉴定了2个吴茱萸碱在大鼠尿液和粪便中的代谢产物(J-3-1和J-3-2)和3个左旋四氢巴马亭在大鼠粪便中的代谢产物(T-1，T-1和Y-3)，并初步推测了3个左旋四氢巴马亭在大鼠粪便中的代谢产物的结构。并对此3个生物碱在微生物与及大鼠体内的代谢途径和代谢产物进行了对比。
Evodia rutaecarpa Juss. Benth is the most important component of famous Wu-Zhu-Yu decoction of China. Previous studies showed that Evodia is effective in the treatment of stomach diseases. Evodiamine and rutaecarpine are the two major active indole alkaloids in the title plant. In recent years, they have been found to exhibit cardiotonic, anti-inflammation and antitumor activities and received more and more attention from scientists of various fields. 1-Tetrahydropalmatine (1-THP), a naturally occurring neuroactive alkaloid from Stephania ainiaca Diels, has been widely used as analgetic medicine-Lu Tong Ding in China for many years. To find more effective compounds with low toxicity or to identify the in vivo metabolites, scientists have been searching for the approach to modify the structures by efficient methods.An important factor in the evaluation of safety and efficacy of any drug is the knowledge of how the drug is metabolized. Microbial metabolic studies have such advantages over chemical synthesis as high stereo- and regio-selectivity and are becoming a complementary tool in the study of drug metabolism in mammals for the reason that most families of human liver cytochrome P450 have been expressed in microorganisms as individual enzymes. For obtaining sizable amount of metabolites for pharmacological and toxicological studies, microbial metabolism is clearly useful.In efforts to study the chemical constituents responsible for antiemetic activity of Evodia and the metabolisms in microbial organism and rats of evodiamine and rutaecarpine, the chemical, pharmacological and metabolic studies were carried out. Metabolism of 1-THP in microbial organisms and rats were investigated at the same time.Two HPLC methods were set up to determinate the concentrations of evodiamine, rutaecarpine, rutaevine and evodin in Evodia, respectively, which get the results of 0.71%, 0.72%, 0.57% and 0.43%. Effects on stomach strips of different fractions of Evodia were evaluated. Fractions a, d and e showed obvious activity of antagoning contraction to stomach. Analgesic effect of different fractions of Evodia was also invesgated using acetic-acid induced twitching in mice and its analgesic potency was compared with ibuprofen. The fractions a, c, d and e all showed potential analgesic effect.
Microbial transformations of evodiamine and rutaecarpine were carried out. Twenty strains of fungi were screened for their capabilities to transform the above two alkaloids. It was found that Mucor, Cunninghamella and Penicilliurn species could metabolize evodiamine and rutaecarpine to produce versatile products. Penicilliumjanthinellum AS 3.510 and Cunningharnella blakesleana AS 3.970 were found to be the most potent strain for evodiamine and rutaecarpine and were selected for the preparative-scale biotransformation. Eight products were isolated from the culture supernatant by silica gel column chromatography and preparative RP-HPLC. By means of extensive spectroscopic techniques, their structures were identified as 10-hydroxyevodiamine (J-3-1), 11- hydroxyevodiamine (J-1), 3-hydroxyevodiamine (J-3-2), p-hydroxybenzyl alcohol (J-2-1), p-hydroxyphenylethyl alcohol (J-2-2), 10-hydroxyrutaecarpine (C-1), 3-hydroxyrutaecarpine (C-2) and 3,10-dihydroxyrutaecarpine (C-6), respectively, among which products J-3-1, J-3-2, J-1, C-1, C-2 and C-6 are new compounds. Two substrates were converted into hydroxyl metabolites in 7 days of incubation with low efficiency and the possible biotransforrnation pathways are proposed to account for the formation of the observed products. The in vitro cytotoxicities of the biotransformed products were determined by MTT method. J-1, J-3-1, J-3-2, C-2 and C-6 were found to exhibit potent inhibitory activities against human cancer cell lines (BGC-823, Bel-7402, MCF-7 and HL-60), in which J-1 showed stronger inhibitory activities against four cell lines than evodiamine.
A similar biotransformation process for 1-THP was carried out. Penicillium janthinellum AS 3.510 was selected as the strain for the preparative-scale biotransformation and 3 products were isolated. Their structures were identified as 1-corydalmine (T-1), 1-corypalmine (T-2) and 9-demethyl-1-THP (T-3), respectively. Time-course investigation revealed that Penicillium janthinellum AS 3.510 could slowly demethylate 1-THP at different -OCH_3 positions.
LC/MS/MS analysis was used in the metabolism studies of evodiamine, rutaecarpine and 1-THP in rats. The structures of two metabolites (J-3-1 and J-3-2) of evodiamine and three metabolites of 1-THP (T-1, T-1 and T-3) in rat urine and feces were identified with the reference standards separated from biotransformation. Structures of three metabolites of 1-THP in rat feces were tentative deduced by MS and MS/MS analysis. The metabolisms of ebodiamine, rutaecarpine and 1-THP in microbial organisms and rats were compared.
引文
[1] 施畅，廖明阳．环磷酰胺与异环磷酰胺在体内的代谢特点分析．解放军药学学报，2001，17(2)：92～94．
[2] 阿基业，王广基．药物代谢研究与药物设计及结构修饰．药学进展，2002，26(2)：80～86．
[3] 刘明杰，林琳，王钊．肠道细菌对天然药物代谢的研究进展Ⅰ．中国现代应用药学杂志，2001，18(2)：90～91．
[4] Swart P J, Oelen, W E, Bruins A R Tepper P G, de Zeeuw R A. 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.
[5] Dogterom P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Dispos., 1993, 21(4): 699～704.
[6] van't Klooster G A, Woutersen-van Nijnanten F M, Kolker H J, Noordhoek J, van Miert A S. Improved high-performance liquid chromatographic method for the determination of ethylmorphine and its metabolites in microsomal incubations and cell culture media. J. Chromatogr., 1992, 579(1): 158～164.
[7] Lhoest G, Maton N, Laurent A, Verbeeck R K. Isolation and identification of a FK-506 C36-C37 dihydrodiol from erythromycin-induced rabbit liver microsomes. J. Pharm. Biomed. Anal., 1994, 12(2): 235～241.
[8] 姚庆强，王慕邹．右旋黄皮酰胺在大鼠肝微粒体中的代谢转化．药学学报，1999，34(4)：303～307．
[9] 薛明，崔颖，张彬，史彦斌，周宗田，罗永江，夏文江，赵荣材．隐丹参酮在猪体内外的代谢转化与抗菌活性．中国兽医学报，1999，19(1)：49～51．
[10] 马海英，周秋丽，王本祥．黄山药总皂苷肠内菌代谢及代谢产物吸收的研究．中国药房，2002，13(4)：204～205．
[11] 唐刚华．稳定同位素法研究川芎哚体内代谢．核技术，2000，23(11)：753～756．
[12] Smith R V, Rosazza J P. Microbial models of mammalian metabolism, aromatic hydroxylation. Arch. Biochem. Biophys., 1974, 161: 551～558.
[13] Azerad R. Microbial models of mammalian metabolism. Adv. Biochem. Eng. Biotechnol., 1999, 63: 169～218.
[14] Isabelle L, Jacques B and Robert A. Microbial models of drug metabolism: microbial transformations of trimegestone (RU27987), a 3-Keto-4,9(10)-19-norsteroid drug. Bioorg. Med. Chem., 1999, 7: 2329～2341.
[15] Moussa C, Houziaux P, Danree B and Azerad R. Microbial models of mammalian metabolism. Fungal metabolism of phenolic and nonphenolic p-cymene-related drugs and prodrugs. Ⅰ. Metabolites of thymoxamine. Drug metab. Dispos., 1997, 25:301～310.
[16] 钦松，周长林．小克银汉酶属的微生物转化在体外药物代谢模型研究中的应用．海峡药学，2004，16(1)：4～8．
[17] 王金辉，李铣．拟人参皂苷F_(11)在大鼠体内的药物代谢研究．药学学报，2001，36(6)：427～431．
[18] 唐刚华．气相色谱-质谱法测定川芎哚血药浓度．药物分析杂志，2000，20(3)：147～148．
[19] 姚庆强，王琰，杨树民，王慕邹．右旋和左旋黄皮酰胺在大鼠体内代谢转化的研究．药学学报，2001，36(3)：224～228．
[20] 阿基业，王广基，柳晓泉，江丹云，刘静涵．高效液相一质谱联用法对盐酸关附甲素在大鼠尿中代谢产物的研究．药学学报，2002，37(4)：283～287．
[21] 孙莹，张宏桂，史向国，段明郁，钟大放．兔体内乌头碱代谢产物研究．药学学报，2002，37(10)：781～783．
[22] 李晓海，张金兰，周同惠．一叶秋碱的高效毛细管电泳手性分离及其大鼠体内立体选择性代谢研究．药学学报，2002，37(1)：50～53．
[23] 杨春，司伊康．药物代谢研究中的核磁共振技术．药物分析杂志，1999，19(6)：422～426．
[24] 徐诗伟．微生物转化在药物合成中的应用前景．中国医药工业杂志，1996，27(9)：422～430．
[25] Aleu J, Collado I G. Biotransformations by Botrytis species. J. Mol. Catal. B-Enzym., 2001, 13: 77z 3.
[26] Grogan G J, Holland H L. The biocatalytic reaction of Beaueria spp. J. Mol. Catal. B-Enzym., 2000, 9 (1): 1～32.
[27] Steineriber A, Faber K. Microbial epoxide hydrolases for preparative biotransformations. Curr. Opin. Biotechnol., 2001, 12: 552～558.
[28] Roberts S M, Wan P W H. Enzyme-catalysed Baeyer-Villiger oxidations. J. Mol. Catal. B-Enzym., 1998, 4: 111～136.
[29] 王云英，徐渡新．生物催化不对称合成研究进展．安徽大学学报，2003，27(3)：103～110．
[30] 陈绍怡，杨秀，秦玉静．手性药物合成中的生物转化．生物工程进展，2000，20(4)：60～64．
[31] 杨柳青，何南，张玉彬．手性药物的生物转化．中国新药杂志，2000，9(12)：817～820．
[32] Smith R V, Rosazza J R Microbial models of mammalian metabolism. J. Pharm. Sci., 1975, 64: 1737～1758.
[33] Clark A M, Hufford C D. Use of microorganisms for the study of drug metabolism: an update. Med. Res. Rev., 1991, 11: 473～501.
[34] Abourashed E A, Clark A M, Hufford C D. Microbial Models of Mammalian Metabolism of Xenobiotics: An Updated Review. Curr. Med. Chem., 1999, 6: 359～374.
[35] Zhang D, Yang Y, Leakey J E, Cemiglia C E. Phase Ⅰ and phase Ⅱ enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbial Lett., 1996, 138: 221～226.
[36] Clark A M, McChesney J D, Hufford C D. The use of microorganisms for the study of drug metabolism. Med. Res. Rev., 1985, 5: 231～253.
[37] Srisilam K, Veeresham C. Biotransformation of drugs by microbial cultures for predicting mammalian drug metabolism. Biotech. Adv., 2003, 21: 3～39.
[38] 刘磊，黄海华，孙璐，钟大放．短刺小克银汉霉菌对维拉帕米转化的能力．中国药理学与毒理学杂志，2002，16(4)：292～298．
[39] Adachi T, Saito M, Sasaki J, Karasawa Y, Araki H, Hanada K, Omura S. Microbial hydroxylation of (-)-eburnamonine by Mucor circinelloides and Strptomyces violens. Chem. Pharm. Bull., 1993, 41: 611～613.
[40] Lacroix I, Biton J, Azerad R. Microbial models of drug metabolism: microbial transformations of Trimegestone (RU27987), a 3-keto-delta(4,9(10))-19-norsteroid drug. Bioorg. Meal. Chem., 1999, 7(11): 2329～2341.
[41] han J X, Guo H Z, Dai J G, Zhang Y X, Guo D A. Microbial transformation of artemisinin by Cunninghamella echinulata and Aspergillus niger. Tetrahedron Lett., 2002, 43:4519～4521.
[42] Zhan J X, Zhang Y X, Guo H Z, Han J, Ning L L, Guo D A. Microbial metabolism of artemisinin by Mucor polymorphosporus and Aspergillus niger. J. Nat. Prod., 2002, 65:1693～1695.
[43] Lee I S, Elsohly H N, Croom E M, Hufford C D. Microbial metabolism studies of the antimalarial sesquiterpene artemisinin. J. Nat. Prod., 1989, 52: 337～341.
[44] Hanson R L, Wasylyk J M, Nanduri V B, Cazzulino D L, Patel R N, Szarka L J. Site-specific enzymatic hydrolysis of taxanes at C-10 and C-13. J. Biol. Chem., 1994, 269: 22145～22149.
[45] Jezequel S G. Microbial models of mammalian metabolism: uses and misuses (clarification of some misconceptions). J. Mol. Catal. B-Enzym., 1998, 5: 371～377.
[46] 叶和春．生物技术在植物药生产中的应用．第五届北京生物医药产业发展论坛．北京，2001，90～93．
[47] 果德安．关于开展中药生物技术研究的几点思考．中国药学科学发展战略与新药研究开发论文集．上海，1999，58～59．
[48] Ye M, Guo D A. Specific 12β-hydroxylation of cinobufagin by filamentous fungi. Appl. Environm. Microb., 2004, 70(6): 3521～3527.
[49] Ye M, Qu G Y, Guo D A. Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure-activity relationships. J. Steroid Biochem. Mol. Biol., 2004, 9: 87～98.
[50] Ning L L, Zhan J X, Zhong L, Li P, Guo H Z, Bi K S, Guo D A. Structural modifications of triptolide by Cunninghamella blakesleana. Tetrahedron. 2003, 59:4209～4213.
[51] Ning L L, Qu G Q, Ye M, Guo H Z, Bi K S, Guo D A. Cytotoxic Biotransformed Products from Triptonide by Aspergillus niger. Planta Med., 2003, 69: 804～808.
[52] Stierle A, Strobel G A, Stuerle D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of pacific yew. Science, 1993,260:214～216.
[53] 林风，程元荣．紫杉醇的生物合成和微生物转化．国外医药抗生素分册，1998，19(1)：22～24．
[54] Rathbone D A, Bruce N C. Microbial transformation of alkaloids. Curr. Opin. Microbiol., 2002, 5: 274～281.
[55] Abraham W R, Spassov G. Biotransformation of alkaloids: a challenge. Heterocycles, 2002, 56: 711～741.
[56] Boonstra B, Rathbone D A, Bruce N C. Engineering novel biocatalytic routes for production of semisynthetic opiate drugs. Biomol. Eng., 2001, 18:41～47.
[57] Lister D L, Kanungo G, Rathbone D A, Bruce N. Transformation of codeine to important semisyntheic opiate derivatives by Pseudomonas putida M 10. FEMS Microbiol. Lett., 1999, 181: 137～144.
[58] Madyastha K, Reddy G, Sridhar G. Transformation of morphine, codeine and their analogues by Bacillus sp. Indian J. Chem. Sect B-Org. Chem. Incl. Med. Chem., 1998, 37: 749～753.
[59] Das B, Madhusudhan P, Venkataiah B. Chemoenzymatic transformation of the natural antitumour alkaloid 20-O-acetylcamptothecin to mappicine ketone and (s)-mappicine. J. Indian Chem. Soc., 1998, 75: 662～665.
[60] Sandrock R W, Vanetten H D. The relevance of tomatinase axtivity in pathogens of tomato: disruption of theβ_2-tomatinase gene in Colletotrichum coccodes and Septoria lycopersici and heterologous expression of the Septoria lycopersici β_2-tomatinase in Nectrial haematococca, a pathogen of tomato fruit. Physiol. Mol. Plant Pathol., 2001, 58: 159～171.
[61] 中华人民共和国卫生部药典委员会编．《中华人民共和国药典》2000年版，一部．北京：化学工业出版社，2000：120．
[62] 鲁燕侠，蔺兴遥，逯振宇，许建阳．吴茱萸的化学成分与临床应用．解放军药学学报，2002，18(4)：218～220．
[63] 小管卓夫．吴茱萸的化学和药理．国外医学．中医中药分册，1986，8(1)：17．
[64] Shoji N, Umeyama A, Iuchi Akio, Saito N, Arihari S. Two novel alkaloids from Evodia rutaecarpa. J. Nat. Prod., 1989, 52(5): 1160～1161.
[65] Shoji N, Umeyama, luchi A, Saito N, Taunematsu T. Isolation of a new alkaloid from Evodia rutaecarpa. J. Nat. Prod., 1988, 51: 791～792.
[66] 唐元清，冯孝章，黄量．吴茱萸化学成分的研究．药学学报，1996，31(2)：151～152．
[67] Guo Y Z, Xiao S Y, Xiao J H. Two new indole alkaloids from Evodia rutaecarpa. Chin. Chem. Lett., 2000, 11(2): 127～128.
[68] Wang Q Z, Liang J Y. Studies on the chemical constituents ofEvodia rutaecarpa (Juss.). Acta Pharmaceut. Sin., 2004, 39(8): 605-608.
[69] 左国营．吴茱萸粉花绣线菊的化学成分及抗菌活性研究．中国科学院博士研究生学位论文，中国科学 院昆明植物研究所，2001，15．
[70] Sugimoto T, Miyase T, Kuroyanagi M, Ueno A. Limonoids and quinolone alkaloids from Evodia rutaecarpa Benthan. Chem. Pham. Bull. 1988, 36(11): 4453～4461.
[71] Yamazaki M, Kawana T. Isolation of hydroxyevdiamine (Rhetsinine) from the fruits of Eodia rutaecarpa. Hook fil. et Thomson. Yakugaku Zasshi-J. Pharm. Soc. Jpn., 1967, 87(5): 608～610.
[72] Ko J S, Rho M C, Chung M Y, Song H Y, Kang J S, Kim K, Lee H S, Kim Y K. Quinolone alkaloids, diacylglycerol acyltransferase inhibitors from the fruits of Evodia rutaecarpa. Planta Med., 2002, 68(12): 1131-1133.
[73] 袁少锋．吴茱萸研究概况．时珍国医国药，2000，11(3)：281～282．
[74] 王锐，倪京满，马腥．中药吴茱萸挥发成分的研究．中国药学杂志，1993，28(1)：16～18．
[75] 阴健，郭弓力．中药现代研究与临床应用．北京：中医药出版社，1993，359～363．
[76] 邱赛红，窦昌贵．吴茱萸汤温胃止呕作用的实验研究．中药药理与临床，1988，4(3)：9～13．
[77] Wu C L, Hung C R, Chang F Y, Lin C L, Pau K Y F, Wang P S. Effects of evodiamine on gastrointestinal motility in male rats. Eur. J. Pharmacol., 2002, 457: 169-176.
[78] 贺玉豚，邹建华．吴茱萸的化学和药理．国外医学中医中药分册，1986，8(1)：17～19．
[79] Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. Anti-invasive and metastativ activeities of evodiamine. Biol. Pharm. Bull., 2002, 25(11): 1491～1493.
[80] Fei X F, Wang B X, Li T J, Tashiro S I, Minami M, Xing D J, lkejima T. Evodiamine, a constituent of Evodiae fructus, induces anti-proliferating effects in tumor cells. Cancer Sci., 2003, 94(1): 93～98.
[81] Zhang Y, Wu L Y, Tashiro S I, Onodera S, Ikejima T. Evodiamine induces tumour cell death through different pathways: apopotosis and necrosis. Acta Phamacol. Sin., 2004, 25(1): 83～89.
[82] Matsuda H, Wu J X, Tanaka T, Iinuma M, Kubo M. Antinociceptive activities of 70% methanal extract of Evodiae fructus (fruit of Evodiae rutaecarpa var. bodinieri) and its alkaloidal components. Biol. Pharm. Bull., 1997, 20(3): 243～248.
[83] 盖玲，盖云，宋纯清，胡之璧．吴茱萸B对大鼠佐剂性关节炎的治疗作用．中成药，2001，23(1)： 807～808.
[84] Matsuda H, Yoshikawa M, Iinuma M, Kubo M. Antinociceptive and anti-inflammatory activities of limonin isolated from the fruits ofEvodia rutaecarpa var. bodinieri. Planta Med., 1998, 64(4): 339～342.
[85] 许青媛，于利森，张小利，陈瑞明，陈春梅．附子、吴茱萸对实验性血栓形成及凝血系统的影响．西北药学杂志，1990，5(2)：9～11．
[86] Yamahara J, Yamada T, Kitani T, Naitoh Y, Fujimura H. Antianoxic action of evodiamine, an alkaloid in Evodia rutaecarpa fruit. J. Ethnopharmacol., 1989, 27:185～192.
[87] 张明发，沈雅琴．吴茱萸的药理作用与其温里功效．天然产物研究与开发，1990，2(4)：59～64．
[88] King C L, Kong Y C, Wong N S, Yeung H W, Fong H H, Sankawa U. Uterotonic effect of Evodia rutaecarpa alkaloids. J. Nat. Prod., 1980, 43(5): 577～582.
[89] Rho T C, Bae E A, Kim D H, Oh W K, Kim B Y, Ahn J S, Lee H S. Anti-Helicobacter pylori activity of quinolone alkaloids from Evodiae Fructus. Biol. Pharm. Bull., 1999, 22(10): 1141～1143.
[90] Hamasaki N, Ishii E, Tominaga K, Tezuka Y, Nagaoka T; Kadota S, Kuroki T; Yano I. Highly selective antibacterial activity of novel alkyl quinolone alkaloids from a Chinese herbal medicine, Gosyuyu (Wu-Chu-Yu), against Helicobacter pylori in vitro. Microbiol. Immunol., 2000, 44(1): 9～15.
[91] Lin H, Tsai S C, Chen J J, Chiao Y C, Wang S W, Wang G J, Chen C F, Wang P S. Effects of evodiamine on the secretion of testosterone in rat testicular interstitial cells. Metabolism, 1999, 48(12): 1532～1535.
[92] Tsai T H, Lee T F, Chen C F, Wang L C H. Thermoregulatory effects of alkaloids isolated from wu-chu-yu in afebrile andfebrile rats. Pharmacol. Biochem. Behav., 1995, 50(2): 293-298.
[93] Kano Y, Zong Q N, Komatsu K. Pharmacological properties of galenical preparation. ⅪⅤ. Body temperature retaining effect of the Chinese traditional medicine, "goshuyu-to" and component crude drugs. Chem. Pharm. Bull., 1991, 39(3): 690～692.
[94] Kobayashi Y, Nakano Y, Kizaki M, Hoshikuma K, Yokoo Y, Kamiya T. Capsaicin-tike anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med., 2001, 67(7): 628～633.
[95] 张韬，张世臣，魏璐雪．吴茱萸及其炮制品中生物碱的含量测定．中国中药杂志，1994，19(7)：409～411．
[96] 庄燕黎．高效液相色谱法测定吴茱萸药材及其制剂中吴茱萸碱和吴茱萸次碱的含量．药物分析杂志，1997，17(3)：174～176．
[97] 赵冬梅，张英，毕开顺．吴茱萸汤不同配伍情况下生物碱含量的RP-HPLC测定．药物分析杂志，1999，19(1)：16～19．
[98] 侯晓虹，于治国．34种吴茱萸碱和吴茱萸次碱的含量测定．沈阳药科大学学报，2000，17(5)：334～337．
[99] Chuang W C. A comparative study on processed Evodia Fructus. The Chin. Pharm. J., 1994, 46: 89.
[100] Chuang W C, Chu C Y, Sheu S J. Determination of the alkaloids in Evodiae Fructus by high performance liquid chromatography. J. Chromatogr. A, 1996, 727: 317～323.
[101] Lee M C, Chuang W C, Sheu S J. Determination of the alkaloids in Evodiae Fructus by capillary electrophoresis. J. Chromatogr. A, 1996, 755:113～119.
[102] 李石蓉，张军平，王红芯，李诒光．中药石虎挥发油成分分析．中药材，1999，22(7)：344～346．
[103] Ko H C, Tsai T H, Chou C J, Hsu S Y, Li S Y, Chen C F. High-performance liquid chromatographic determination of rutaecarpine in rat plasma: application to a pharmacokinetic study. J. Chromatogr. B, 1994, 655: 27～31.
[104] Jeng K F, Lin Y H, Lin L C, Chou C J, Tsai T H, Chen C F. High-performance liquid chromatographic determination of evodiamine in rat plasma: application to a pharmacokinetic study. J. Chromatogr. B, 1995, 668: 343～345.
[105] Komatsu K, Wakame K; Kano Y. Pharmacological properties of galenical preparation. Ⅹ Ⅵ. Pharmacokinetics of evodiamine and the metabolite in rats. Yakugaku Zasshi-J. Pharm. Soc. Jpn., 1993, 16(9): 935～938.
[106] Ueng Y F, Don M J, Peng H C, Wang S Y, Wang J J, Chen C F. Effects of wu-chu-yu-tang and its component herbs on drug-metabolizing enzymes. Jpn. J. Pharmacol., 2002, 89: 267～273.
[107] Ueng Y F, Ko H C, Chen C F, Wang J J, Chen K T. Modulation of drug-metabolizing enzymes by extracts of a herbal medicine Evodia rutaecarpa in C57BL/6J mice. Life Sci., 2002, 71: 1267～1277.
[108] Ueng Y F, Wang J J, Lin L C, Park S S, Chen C F. Induction of cytochrome P450-dependent monooxygense in mouse liver and kidney by rutaecarpine, an alkaloid of the herbal drug Evodia rutaecarpa. Life Sci., 2001, 70:207～217.
[109] 王浴生主编，中药药理与应用，人民卫生出版社，1983，447．
[110] 南京要学院《中草药学》编写组．中草药学(中册)．浙江：江苏人民出版社，1976：340．
[111] 刘国卿，马志清．四氢巴马汀等单胺排空作用的比较．药学学报，1988，23(10)：721～726．
[112] 金国章，王月娥，胥彬．延胡索乙素旋光异构体和四氢小檗碱对脊髓活动的影响．生理学报，1980，32(2)：110～116．
[113] 马志清，刘国卿．四氢巴马汀等喹啉生物碱对突触体及囊泡摄取[~3H]多巴胺的影响．药学学报，1987，22(5)：335～340．
[114] 金国章，许守玺，俞蕾平．四氢巴马汀旋光异构体对脑内多巴胺能系统的不同药理作用．中国科学B辑，1985．11：1015～1022．
[115] 金国章．左旋四氢巴马汀和他的第二代新药-左旋千金滕啶碱的药理研究进展．药学学报，1987，22：472～480．
[116] 赵东科，赵更生，邱培伦，李孝光，赵永强．四氢巴马汀对家兔窦房结和豚鼠心肌慢反应电活动的影响．中国药理学与毒理学杂志，1988，2(3)：178～182．
[117] 刘耕陶，雷海鹏．延胡索乙素对大鼠垂体促肾上腺皮质激素(ACTH)分泌的刺激作用．药学学报，1963，10(8)：474～479．
[118] 刘耕陶，诸亚军，雷海鹏．小檗碱，巴马亭及四氢巴马亭(延胡索乙素)对大鼠促皮质激素释放的影响．药学学报，1966，13(5)：356～361．
[119] 吴绍光，李晓兰，赵国举．左旋四氢巴马汀对几种激动剂所致气管收缩作用的影响．中国药理学通报，1990，6(3)：179～181．
[120] 赵东科，赵更生，邱培伦，明祯．dl-四氢巴马汀在子宫平滑肌上的钙拮抗作用．西安医科大学学报，1990，11(3)：217～220．
[121] 常新全，丁丽霞主编．中药活性成分分析手册．北京：学苑出版社，852．
[122] 赵岚，倪晟，章曙丹，吴妙爱．薄层扫描法测定痛经宁贴剂中延胡索乙素的含量．江苏药学与临床研究，1998，6(4)：24～25．
[123] 王杰，李建，吕归宝．薄层扫描法测定真心平胶囊中延胡索乙素含量．中草药，1999，30(7)：505～506．
[124] 倪晟，徐强，章曙丹．薄层扫描法测定元胡止痛片中延胡索乙素的含量．中国现代应用药学杂志，2000，17(5)：368～369．
[125] 杨天展．高效液相色谱法测定胃得康散中延胡索乙素含量．时珍国医国药，2000，11(1)：31～32．
[126] 龚青，周蒂，王碧娟．HPLC法测定延胡索中延胡索乙素的含量．中国现代应用药学，2000，17(4)：315-317
[127] 高长清，王培军，宋步昌，邵新．高效液相色谱法测定元胡止痛片中延胡索乙素的含量．山东中医杂志，2003，22(6)：365～366．
[128] 张强，柳全文，田景振．高效毛细管区带电泳测定克心疼缓释片中的延胡索乙素，药物分析杂志，2001，21(1)：53～55．
[129] 姜舜尧．高效液相色谱法测定元胡止痛片中脱氢延胡索碱的含量．中国中药杂志，2000，25(8)：479～512．
[130] 虞清，徐国均，金蓉鸾，徐珞珊，丛晓东．中药延胡索类研究．4种延胡索块茎中生物碱的含量比较．中国药科大学学报，1988，19(1)：4～7．
[131] Lai C H, Albert C Y W. Tetrahydropalmatine poisoning: Diagnoses of nine adult overdoses based on toxicology screens by HPLC with diode-array detection and Gas chromatography-Mass spectrometry, Clin. Chem., 1999, 45(2): 229～236.
[132] 黄建明，郭济贤．中国干金藤属(Stephania)植物中生物碱类化学成分的研究进展．华西药学杂志，1998，13(2)：97～99．
[133] 马养民．千斤藤属植物化学成分研究．西北林学院学报，2004，19(3)：125～130．
[134] 金国章，胡江元．颅痛定的镇痛作用机制与多巴胺受体-中药延胡索研究的系统论坛．药理学进展．金正均，王永铭，苏定冯主编，北京：科学出版社，1999：64～73．
[135] Huang K, Dai G Z, Li X H, Fan Q, Cheng L, Feng Y B, Xia J Z, Yao W X. Blocking L-calcium current by l-tetrahydropalmatine in single ventricular myocyte of guinea pigs. Acta Pharmacol. Sin., 1999, 20(10): 907～911.
[136] 汪永孝，郑云敏，谭月华．四氢巴马亭抗缺血再灌注心率失常的作用及其机理．中国药理学通报，1993，9(5)：358～361．
[137] 刘家兰，刘红．左旋四氢帕马丁对外源性自由基加速大鼠心脏再灌注损伤的保护作用．中国药学杂志，1994，29(8)：462～464．
[138] Zhang Q, Zhu W, Cao L, Liu F. Effects of L-THP on Ca~(2+) overload of cultured rat cardiomycocytes during hypoxia and reoxygenation. J. Tongji Med. Uni., 2000, 20(4): 294-296.
[139] Yang G, Jiang C, Tang Y, Wang P. Effects of L-tratrohydropalmatine on neuron apoptosis during acute cerebral ischemia-reperfusion of rats. J. Tongji Medi. Uni., 2000, 20(2): 106～108.
[140] 邵翎宁，颜洁明，颜梅，卞春甫．左旋四氢巴马亭对门静脉压的影响及其机制．中国药理学通报，1995，11(3)：248～250．
[141] 邵翎宁，颜洁明，颜梅．左旋四氢巴马亭对肝硬化门静脉高压和胰高糖素的影响．徐州医学院学报，1995，15(1)：9～11．
[142] 罗东，代青，管明银．速效枣仁安神胶囊中左旋延胡索乙素的定性鉴别及含量测定．药学实践杂志，1999，17(4)：233～235．
[143] 李丽清，杨敏丽，封满良，吕九如．流动注射化学发光法测定罗通定中延胡索乙素．分析化学，1997，25(11)：1321～1323．
[144] 张金凤，谭力，周继红，陆晓和，袁倚盛．HPLC测定人血浆中罗痛定浓度及药代动力学研究．中国药科大学学报，1998，29(1)：67～70．
[145] 张文伟，余伯阳，彭娟．左旋四氢巴马亭生物转化为左旋紫堇达明的研究．药物生物技术，2003，10(3)：165～168．
[146] 宣建成，林光大，金国章等．4种四氢原小檗碱同类物的立体结构和量子化学对多巴胺受体的作用关系．中国药理学报，1988，9(3)：197～205．
[147] 于治国，侯晓虹，时雅曼，马俊凤，毕开顺．HPLC测定吴茱萸及制剂中吴茱萸碱和吴茱萸次碱含量．中国药学杂志，1999，34(10)：691～693．
[148] 甄攀，杨凤珍．吴茱萸总生物碱提取条件的研究．分析仪器，2000，2：27～29．
[149] 宋建徽，孟祥琴，苏素文，郭鸣放，王川，苗庆峰，任雷鸣．安胃降逆饮对大鼠胃功能的影响．河北医科大学学报，2000，21(4)：202～204．
[150] 张虎，杨秀伟，崔育新．吴茱萸碱吴茱萸次碱和去氢吴茱萸碱的碳氢NMR信号全指定．波谱学杂志，1999，16(6)：563～567．
[151] 于德泉，杨俊山．《分析化学手册，核磁共振波谱分册》．北京：化学工业出版社，1999，690．
[152] 陈嬿，方圣鼎，磯具，彰铃木，昭惠．千金藤属植物小叶地不容中的生物碱(Ⅷ)．植物学报，1889，31(7)：544～548．
[153] Tetsuji K, keiichiro F, Masataka I, Akira U. Conformational analysis of the dibenzo[a,g]quinolizidines by spectroscopic methods. J. Org. Chem., 1975, 40 (22): 3280～3283.
[2] 阿基业，王广基．药物代谢研究与药物设计及结构修饰．药学进展，2002，26(2)：80～86．
[3] 刘明杰，林琳，王钊．肠道细菌对天然药物代谢的研究进展Ⅰ．中国现代应用药学杂志，2001，18(2)：90～91．
[4] Swart P J, Oelen, W E, Bruins A R Tepper P G, de Zeeuw R A. 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.
[5] Dogterom P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Dispos., 1993, 21(4): 699～704.
[6] van't Klooster G A, Woutersen-van Nijnanten F M, Kolker H J, Noordhoek J, van Miert A S. Improved high-performance liquid chromatographic method for the determination of ethylmorphine and its metabolites in microsomal incubations and cell culture media. J. Chromatogr., 1992, 579(1): 158～164.
[7] Lhoest G, Maton N, Laurent A, Verbeeck R K. Isolation and identification of a FK-506 C36-C37 dihydrodiol from erythromycin-induced rabbit liver microsomes. J. Pharm. Biomed. Anal., 1994, 12(2): 235～241.
[8] 姚庆强，王慕邹．右旋黄皮酰胺在大鼠肝微粒体中的代谢转化．药学学报，1999，34(4)：303～307．
[9] 薛明，崔颖，张彬，史彦斌，周宗田，罗永江，夏文江，赵荣材．隐丹参酮在猪体内外的代谢转化与抗菌活性．中国兽医学报，1999，19(1)：49～51．
[10] 马海英，周秋丽，王本祥．黄山药总皂苷肠内菌代谢及代谢产物吸收的研究．中国药房，2002，13(4)：204～205．
[11] 唐刚华．稳定同位素法研究川芎哚体内代谢．核技术，2000，23(11)：753～756．
[12] Smith R V, Rosazza J P. Microbial models of mammalian metabolism, aromatic hydroxylation. Arch. Biochem. Biophys., 1974, 161: 551～558.
[13] Azerad R. Microbial models of mammalian metabolism. Adv. Biochem. Eng. Biotechnol., 1999, 63: 169～218.
[14] Isabelle L, Jacques B and Robert A. Microbial models of drug metabolism: microbial transformations of trimegestone (RU27987), a 3-Keto-4,9(10)-19-norsteroid drug. Bioorg. Med. Chem., 1999, 7: 2329～2341.
[15] Moussa C, Houziaux P, Danree B and Azerad R. Microbial models of mammalian metabolism. Fungal metabolism of phenolic and nonphenolic p-cymene-related drugs and prodrugs. Ⅰ. Metabolites of thymoxamine. Drug metab. Dispos., 1997, 25:301～310.
[16] 钦松，周长林．小克银汉酶属的微生物转化在体外药物代谢模型研究中的应用．海峡药学，2004，16(1)：4～8．
[17] 王金辉，李铣．拟人参皂苷F_(11)在大鼠体内的药物代谢研究．药学学报，2001，36(6)：427～431．
[18] 唐刚华．气相色谱-质谱法测定川芎哚血药浓度．药物分析杂志，2000，20(3)：147～148．
[19] 姚庆强，王琰，杨树民，王慕邹．右旋和左旋黄皮酰胺在大鼠体内代谢转化的研究．药学学报，2001，36(3)：224～228．
[20] 阿基业，王广基，柳晓泉，江丹云，刘静涵．高效液相一质谱联用法对盐酸关附甲素在大鼠尿中代谢产物的研究．药学学报，2002，37(4)：283～287．
[21] 孙莹，张宏桂，史向国，段明郁，钟大放．兔体内乌头碱代谢产物研究．药学学报，2002，37(10)：781～783．
[22] 李晓海，张金兰，周同惠．一叶秋碱的高效毛细管电泳手性分离及其大鼠体内立体选择性代谢研究．药学学报，2002，37(1)：50～53．
[23] 杨春，司伊康．药物代谢研究中的核磁共振技术．药物分析杂志，1999，19(6)：422～426．
[24] 徐诗伟．微生物转化在药物合成中的应用前景．中国医药工业杂志，1996，27(9)：422～430．
[25] Aleu J, Collado I G. Biotransformations by Botrytis species. J. Mol. Catal. B-Enzym., 2001, 13: 77z 3.
[26] Grogan G J, Holland H L. The biocatalytic reaction of Beaueria spp. J. Mol. Catal. B-Enzym., 2000, 9 (1): 1～32.
[27] Steineriber A, Faber K. Microbial epoxide hydrolases for preparative biotransformations. Curr. Opin. Biotechnol., 2001, 12: 552～558.
[28] Roberts S M, Wan P W H. Enzyme-catalysed Baeyer-Villiger oxidations. J. Mol. Catal. B-Enzym., 1998, 4: 111～136.
[29] 王云英，徐渡新．生物催化不对称合成研究进展．安徽大学学报，2003，27(3)：103～110．
[30] 陈绍怡，杨秀，秦玉静．手性药物合成中的生物转化．生物工程进展，2000，20(4)：60～64．
[31] 杨柳青，何南，张玉彬．手性药物的生物转化．中国新药杂志，2000，9(12)：817～820．
[32] Smith R V, Rosazza J R Microbial models of mammalian metabolism. J. Pharm. Sci., 1975, 64: 1737～1758.
[33] Clark A M, Hufford C D. Use of microorganisms for the study of drug metabolism: an update. Med. Res. Rev., 1991, 11: 473～501.
[34] Abourashed E A, Clark A M, Hufford C D. Microbial Models of Mammalian Metabolism of Xenobiotics: An Updated Review. Curr. Med. Chem., 1999, 6: 359～374.
[35] Zhang D, Yang Y, Leakey J E, Cemiglia C E. Phase Ⅰ and phase Ⅱ enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbial Lett., 1996, 138: 221～226.
[36] Clark A M, McChesney J D, Hufford C D. The use of microorganisms for the study of drug metabolism. Med. Res. Rev., 1985, 5: 231～253.
[37] Srisilam K, Veeresham C. Biotransformation of drugs by microbial cultures for predicting mammalian drug metabolism. Biotech. Adv., 2003, 21: 3～39.
[38] 刘磊，黄海华，孙璐，钟大放．短刺小克银汉霉菌对维拉帕米转化的能力．中国药理学与毒理学杂志，2002，16(4)：292～298．
[39] Adachi T, Saito M, Sasaki J, Karasawa Y, Araki H, Hanada K, Omura S. Microbial hydroxylation of (-)-eburnamonine by Mucor circinelloides and Strptomyces violens. Chem. Pharm. Bull., 1993, 41: 611～613.
[40] Lacroix I, Biton J, Azerad R. Microbial models of drug metabolism: microbial transformations of Trimegestone (RU27987), a 3-keto-delta(4,9(10))-19-norsteroid drug. Bioorg. Meal. Chem., 1999, 7(11): 2329～2341.
[41] han J X, Guo H Z, Dai J G, Zhang Y X, Guo D A. Microbial transformation of artemisinin by Cunninghamella echinulata and Aspergillus niger. Tetrahedron Lett., 2002, 43:4519～4521.
[42] Zhan J X, Zhang Y X, Guo H Z, Han J, Ning L L, Guo D A. Microbial metabolism of artemisinin by Mucor polymorphosporus and Aspergillus niger. J. Nat. Prod., 2002, 65:1693～1695.
[43] Lee I S, Elsohly H N, Croom E M, Hufford C D. Microbial metabolism studies of the antimalarial sesquiterpene artemisinin. J. Nat. Prod., 1989, 52: 337～341.
[44] Hanson R L, Wasylyk J M, Nanduri V B, Cazzulino D L, Patel R N, Szarka L J. Site-specific enzymatic hydrolysis of taxanes at C-10 and C-13. J. Biol. Chem., 1994, 269: 22145～22149.
[45] Jezequel S G. Microbial models of mammalian metabolism: uses and misuses (clarification of some misconceptions). J. Mol. Catal. B-Enzym., 1998, 5: 371～377.
[46] 叶和春．生物技术在植物药生产中的应用．第五届北京生物医药产业发展论坛．北京，2001，90～93．
[47] 果德安．关于开展中药生物技术研究的几点思考．中国药学科学发展战略与新药研究开发论文集．上海，1999，58～59．
[48] Ye M, Guo D A. Specific 12β-hydroxylation of cinobufagin by filamentous fungi. Appl. Environm. Microb., 2004, 70(6): 3521～3527.
[49] Ye M, Qu G Y, Guo D A. Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure-activity relationships. J. Steroid Biochem. Mol. Biol., 2004, 9: 87～98.
[50] Ning L L, Zhan J X, Zhong L, Li P, Guo H Z, Bi K S, Guo D A. Structural modifications of triptolide by Cunninghamella blakesleana. Tetrahedron. 2003, 59:4209～4213.
[51] Ning L L, Qu G Q, Ye M, Guo H Z, Bi K S, Guo D A. Cytotoxic Biotransformed Products from Triptonide by Aspergillus niger. Planta Med., 2003, 69: 804～808.
[52] Stierle A, Strobel G A, Stuerle D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of pacific yew. Science, 1993,260:214～216.
[53] 林风，程元荣．紫杉醇的生物合成和微生物转化．国外医药抗生素分册，1998，19(1)：22～24．
[54] Rathbone D A, Bruce N C. Microbial transformation of alkaloids. Curr. Opin. Microbiol., 2002, 5: 274～281.
[55] Abraham W R, Spassov G. Biotransformation of alkaloids: a challenge. Heterocycles, 2002, 56: 711～741.
[56] Boonstra B, Rathbone D A, Bruce N C. Engineering novel biocatalytic routes for production of semisynthetic opiate drugs. Biomol. Eng., 2001, 18:41～47.
[57] Lister D L, Kanungo G, Rathbone D A, Bruce N. Transformation of codeine to important semisyntheic opiate derivatives by Pseudomonas putida M 10. FEMS Microbiol. Lett., 1999, 181: 137～144.
[58] Madyastha K, Reddy G, Sridhar G. Transformation of morphine, codeine and their analogues by Bacillus sp. Indian J. Chem. Sect B-Org. Chem. Incl. Med. Chem., 1998, 37: 749～753.
[59] Das B, Madhusudhan P, Venkataiah B. Chemoenzymatic transformation of the natural antitumour alkaloid 20-O-acetylcamptothecin to mappicine ketone and (s)-mappicine. J. Indian Chem. Soc., 1998, 75: 662～665.
[60] Sandrock R W, Vanetten H D. The relevance of tomatinase axtivity in pathogens of tomato: disruption of theβ_2-tomatinase gene in Colletotrichum coccodes and Septoria lycopersici and heterologous expression of the Septoria lycopersici β_2-tomatinase in Nectrial haematococca, a pathogen of tomato fruit. Physiol. Mol. Plant Pathol., 2001, 58: 159～171.
[61] 中华人民共和国卫生部药典委员会编．《中华人民共和国药典》2000年版，一部．北京：化学工业出版社，2000：120．
[62] 鲁燕侠，蔺兴遥，逯振宇，许建阳．吴茱萸的化学成分与临床应用．解放军药学学报，2002，18(4)：218～220．
[63] 小管卓夫．吴茱萸的化学和药理．国外医学．中医中药分册，1986，8(1)：17．
[64] Shoji N, Umeyama A, Iuchi Akio, Saito N, Arihari S. Two novel alkaloids from Evodia rutaecarpa. J. Nat. Prod., 1989, 52(5): 1160～1161.
[65] Shoji N, Umeyama, luchi A, Saito N, Taunematsu T. Isolation of a new alkaloid from Evodia rutaecarpa. J. Nat. Prod., 1988, 51: 791～792.
[66] 唐元清，冯孝章，黄量．吴茱萸化学成分的研究．药学学报，1996，31(2)：151～152．
[67] Guo Y Z, Xiao S Y, Xiao J H. Two new indole alkaloids from Evodia rutaecarpa. Chin. Chem. Lett., 2000, 11(2): 127～128.
[68] Wang Q Z, Liang J Y. Studies on the chemical constituents ofEvodia rutaecarpa (Juss.). Acta Pharmaceut. Sin., 2004, 39(8): 605-608.
[69] 左国营．吴茱萸粉花绣线菊的化学成分及抗菌活性研究．中国科学院博士研究生学位论文，中国科学 院昆明植物研究所，2001，15．
[70] Sugimoto T, Miyase T, Kuroyanagi M, Ueno A. Limonoids and quinolone alkaloids from Evodia rutaecarpa Benthan. Chem. Pham. Bull. 1988, 36(11): 4453～4461.
[71] Yamazaki M, Kawana T. Isolation of hydroxyevdiamine (Rhetsinine) from the fruits of Eodia rutaecarpa. Hook fil. et Thomson. Yakugaku Zasshi-J. Pharm. Soc. Jpn., 1967, 87(5): 608～610.
[72] Ko J S, Rho M C, Chung M Y, Song H Y, Kang J S, Kim K, Lee H S, Kim Y K. Quinolone alkaloids, diacylglycerol acyltransferase inhibitors from the fruits of Evodia rutaecarpa. Planta Med., 2002, 68(12): 1131-1133.
[73] 袁少锋．吴茱萸研究概况．时珍国医国药，2000，11(3)：281～282．
[74] 王锐，倪京满，马腥．中药吴茱萸挥发成分的研究．中国药学杂志，1993，28(1)：16～18．
[75] 阴健，郭弓力．中药现代研究与临床应用．北京：中医药出版社，1993，359～363．
[76] 邱赛红，窦昌贵．吴茱萸汤温胃止呕作用的实验研究．中药药理与临床，1988，4(3)：9～13．
[77] Wu C L, Hung C R, Chang F Y, Lin C L, Pau K Y F, Wang P S. Effects of evodiamine on gastrointestinal motility in male rats. Eur. J. Pharmacol., 2002, 457: 169-176.
[78] 贺玉豚，邹建华．吴茱萸的化学和药理．国外医学中医中药分册，1986，8(1)：17～19．
[79] Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. Anti-invasive and metastativ activeities of evodiamine. Biol. Pharm. Bull., 2002, 25(11): 1491～1493.
[80] Fei X F, Wang B X, Li T J, Tashiro S I, Minami M, Xing D J, lkejima T. Evodiamine, a constituent of Evodiae fructus, induces anti-proliferating effects in tumor cells. Cancer Sci., 2003, 94(1): 93～98.
[81] Zhang Y, Wu L Y, Tashiro S I, Onodera S, Ikejima T. Evodiamine induces tumour cell death through different pathways: apopotosis and necrosis. Acta Phamacol. Sin., 2004, 25(1): 83～89.
[82] Matsuda H, Wu J X, Tanaka T, Iinuma M, Kubo M. Antinociceptive activities of 70% methanal extract of Evodiae fructus (fruit of Evodiae rutaecarpa var. bodinieri) and its alkaloidal components. Biol. Pharm. Bull., 1997, 20(3): 243～248.
[83] 盖玲，盖云，宋纯清，胡之璧．吴茱萸B对大鼠佐剂性关节炎的治疗作用．中成药，2001，23(1)： 807～808.
[84] Matsuda H, Yoshikawa M, Iinuma M, Kubo M. Antinociceptive and anti-inflammatory activities of limonin isolated from the fruits ofEvodia rutaecarpa var. bodinieri. Planta Med., 1998, 64(4): 339～342.
[85] 许青媛，于利森，张小利，陈瑞明，陈春梅．附子、吴茱萸对实验性血栓形成及凝血系统的影响．西北药学杂志，1990，5(2)：9～11．
[86] Yamahara J, Yamada T, Kitani T, Naitoh Y, Fujimura H. Antianoxic action of evodiamine, an alkaloid in Evodia rutaecarpa fruit. J. Ethnopharmacol., 1989, 27:185～192.
[87] 张明发，沈雅琴．吴茱萸的药理作用与其温里功效．天然产物研究与开发，1990，2(4)：59～64．
[88] King C L, Kong Y C, Wong N S, Yeung H W, Fong H H, Sankawa U. Uterotonic effect of Evodia rutaecarpa alkaloids. J. Nat. Prod., 1980, 43(5): 577～582.
[89] Rho T C, Bae E A, Kim D H, Oh W K, Kim B Y, Ahn J S, Lee H S. Anti-Helicobacter pylori activity of quinolone alkaloids from Evodiae Fructus. Biol. Pharm. Bull., 1999, 22(10): 1141～1143.
[90] Hamasaki N, Ishii E, Tominaga K, Tezuka Y, Nagaoka T; Kadota S, Kuroki T; Yano I. Highly selective antibacterial activity of novel alkyl quinolone alkaloids from a Chinese herbal medicine, Gosyuyu (Wu-Chu-Yu), against Helicobacter pylori in vitro. Microbiol. Immunol., 2000, 44(1): 9～15.
[91] Lin H, Tsai S C, Chen J J, Chiao Y C, Wang S W, Wang G J, Chen C F, Wang P S. Effects of evodiamine on the secretion of testosterone in rat testicular interstitial cells. Metabolism, 1999, 48(12): 1532～1535.
[92] Tsai T H, Lee T F, Chen C F, Wang L C H. Thermoregulatory effects of alkaloids isolated from wu-chu-yu in afebrile andfebrile rats. Pharmacol. Biochem. Behav., 1995, 50(2): 293-298.
[93] Kano Y, Zong Q N, Komatsu K. Pharmacological properties of galenical preparation. ⅪⅤ. Body temperature retaining effect of the Chinese traditional medicine, "goshuyu-to" and component crude drugs. Chem. Pharm. Bull., 1991, 39(3): 690～692.
[94] Kobayashi Y, Nakano Y, Kizaki M, Hoshikuma K, Yokoo Y, Kamiya T. Capsaicin-tike anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med., 2001, 67(7): 628～633.
[95] 张韬，张世臣，魏璐雪．吴茱萸及其炮制品中生物碱的含量测定．中国中药杂志，1994，19(7)：409～411．
[96] 庄燕黎．高效液相色谱法测定吴茱萸药材及其制剂中吴茱萸碱和吴茱萸次碱的含量．药物分析杂志，1997，17(3)：174～176．
[97] 赵冬梅，张英，毕开顺．吴茱萸汤不同配伍情况下生物碱含量的RP-HPLC测定．药物分析杂志，1999，19(1)：16～19．
[98] 侯晓虹，于治国．34种吴茱萸碱和吴茱萸次碱的含量测定．沈阳药科大学学报，2000，17(5)：334～337．
[99] Chuang W C. A comparative study on processed Evodia Fructus. The Chin. Pharm. J., 1994, 46: 89.
[100] Chuang W C, Chu C Y, Sheu S J. Determination of the alkaloids in Evodiae Fructus by high performance liquid chromatography. J. Chromatogr. A, 1996, 727: 317～323.
[101] Lee M C, Chuang W C, Sheu S J. Determination of the alkaloids in Evodiae Fructus by capillary electrophoresis. J. Chromatogr. A, 1996, 755:113～119.
[102] 李石蓉，张军平，王红芯，李诒光．中药石虎挥发油成分分析．中药材，1999，22(7)：344～346．
[103] Ko H C, Tsai T H, Chou C J, Hsu S Y, Li S Y, Chen C F. High-performance liquid chromatographic determination of rutaecarpine in rat plasma: application to a pharmacokinetic study. J. Chromatogr. B, 1994, 655: 27～31.
[104] Jeng K F, Lin Y H, Lin L C, Chou C J, Tsai T H, Chen C F. High-performance liquid chromatographic determination of evodiamine in rat plasma: application to a pharmacokinetic study. J. Chromatogr. B, 1995, 668: 343～345.
[105] Komatsu K, Wakame K; Kano Y. Pharmacological properties of galenical preparation. Ⅹ Ⅵ. Pharmacokinetics of evodiamine and the metabolite in rats. Yakugaku Zasshi-J. Pharm. Soc. Jpn., 1993, 16(9): 935～938.
[106] Ueng Y F, Don M J, Peng H C, Wang S Y, Wang J J, Chen C F. Effects of wu-chu-yu-tang and its component herbs on drug-metabolizing enzymes. Jpn. J. Pharmacol., 2002, 89: 267～273.
[107] Ueng Y F, Ko H C, Chen C F, Wang J J, Chen K T. Modulation of drug-metabolizing enzymes by extracts of a herbal medicine Evodia rutaecarpa in C57BL/6J mice. Life Sci., 2002, 71: 1267～1277.
[108] Ueng Y F, Wang J J, Lin L C, Park S S, Chen C F. Induction of cytochrome P450-dependent monooxygense in mouse liver and kidney by rutaecarpine, an alkaloid of the herbal drug Evodia rutaecarpa. Life Sci., 2001, 70:207～217.
[109] 王浴生主编，中药药理与应用，人民卫生出版社，1983，447．
[110] 南京要学院《中草药学》编写组．中草药学(中册)．浙江：江苏人民出版社，1976：340．
[111] 刘国卿，马志清．四氢巴马汀等单胺排空作用的比较．药学学报，1988，23(10)：721～726．
[112] 金国章，王月娥，胥彬．延胡索乙素旋光异构体和四氢小檗碱对脊髓活动的影响．生理学报，1980，32(2)：110～116．
[113] 马志清，刘国卿．四氢巴马汀等喹啉生物碱对突触体及囊泡摄取[~3H]多巴胺的影响．药学学报，1987，22(5)：335～340．
[114] 金国章，许守玺，俞蕾平．四氢巴马汀旋光异构体对脑内多巴胺能系统的不同药理作用．中国科学B辑，1985．11：1015～1022．
[115] 金国章．左旋四氢巴马汀和他的第二代新药-左旋千金滕啶碱的药理研究进展．药学学报，1987，22：472～480．
[116] 赵东科，赵更生，邱培伦，李孝光，赵永强．四氢巴马汀对家兔窦房结和豚鼠心肌慢反应电活动的影响．中国药理学与毒理学杂志，1988，2(3)：178～182．
[117] 刘耕陶，雷海鹏．延胡索乙素对大鼠垂体促肾上腺皮质激素(ACTH)分泌的刺激作用．药学学报，1963，10(8)：474～479．
[118] 刘耕陶，诸亚军，雷海鹏．小檗碱，巴马亭及四氢巴马亭(延胡索乙素)对大鼠促皮质激素释放的影响．药学学报，1966，13(5)：356～361．
[119] 吴绍光，李晓兰，赵国举．左旋四氢巴马汀对几种激动剂所致气管收缩作用的影响．中国药理学通报，1990，6(3)：179～181．
[120] 赵东科，赵更生，邱培伦，明祯．dl-四氢巴马汀在子宫平滑肌上的钙拮抗作用．西安医科大学学报，1990，11(3)：217～220．
[121] 常新全，丁丽霞主编．中药活性成分分析手册．北京：学苑出版社，852．
[122] 赵岚，倪晟，章曙丹，吴妙爱．薄层扫描法测定痛经宁贴剂中延胡索乙素的含量．江苏药学与临床研究，1998，6(4)：24～25．
[123] 王杰，李建，吕归宝．薄层扫描法测定真心平胶囊中延胡索乙素含量．中草药，1999，30(7)：505～506．
[124] 倪晟，徐强，章曙丹．薄层扫描法测定元胡止痛片中延胡索乙素的含量．中国现代应用药学杂志，2000，17(5)：368～369．
[125] 杨天展．高效液相色谱法测定胃得康散中延胡索乙素含量．时珍国医国药，2000，11(1)：31～32．
[126] 龚青，周蒂，王碧娟．HPLC法测定延胡索中延胡索乙素的含量．中国现代应用药学，2000，17(4)：315-317
[127] 高长清，王培军，宋步昌，邵新．高效液相色谱法测定元胡止痛片中延胡索乙素的含量．山东中医杂志，2003，22(6)：365～366．
[128] 张强，柳全文，田景振．高效毛细管区带电泳测定克心疼缓释片中的延胡索乙素，药物分析杂志，2001，21(1)：53～55．
[129] 姜舜尧．高效液相色谱法测定元胡止痛片中脱氢延胡索碱的含量．中国中药杂志，2000，25(8)：479～512．
[130] 虞清，徐国均，金蓉鸾，徐珞珊，丛晓东．中药延胡索类研究．4种延胡索块茎中生物碱的含量比较．中国药科大学学报，1988，19(1)：4～7．
[131] Lai C H, Albert C Y W. Tetrahydropalmatine poisoning: Diagnoses of nine adult overdoses based on toxicology screens by HPLC with diode-array detection and Gas chromatography-Mass spectrometry, Clin. Chem., 1999, 45(2): 229～236.
[132] 黄建明，郭济贤．中国干金藤属(Stephania)植物中生物碱类化学成分的研究进展．华西药学杂志，1998，13(2)：97～99．
[133] 马养民．千斤藤属植物化学成分研究．西北林学院学报，2004，19(3)：125～130．
[134] 金国章，胡江元．颅痛定的镇痛作用机制与多巴胺受体-中药延胡索研究的系统论坛．药理学进展．金正均，王永铭，苏定冯主编，北京：科学出版社，1999：64～73．
[135] Huang K, Dai G Z, Li X H, Fan Q, Cheng L, Feng Y B, Xia J Z, Yao W X. Blocking L-calcium current by l-tetrahydropalmatine in single ventricular myocyte of guinea pigs. Acta Pharmacol. Sin., 1999, 20(10): 907～911.
[136] 汪永孝，郑云敏，谭月华．四氢巴马亭抗缺血再灌注心率失常的作用及其机理．中国药理学通报，1993，9(5)：358～361．
[137] 刘家兰，刘红．左旋四氢帕马丁对外源性自由基加速大鼠心脏再灌注损伤的保护作用．中国药学杂志，1994，29(8)：462～464．
[138] Zhang Q, Zhu W, Cao L, Liu F. Effects of L-THP on Ca~(2+) overload of cultured rat cardiomycocytes during hypoxia and reoxygenation. J. Tongji Med. Uni., 2000, 20(4): 294-296.
[139] Yang G, Jiang C, Tang Y, Wang P. Effects of L-tratrohydropalmatine on neuron apoptosis during acute cerebral ischemia-reperfusion of rats. J. Tongji Medi. Uni., 2000, 20(2): 106～108.
[140] 邵翎宁，颜洁明，颜梅，卞春甫．左旋四氢巴马亭对门静脉压的影响及其机制．中国药理学通报，1995，11(3)：248～250．
[141] 邵翎宁，颜洁明，颜梅．左旋四氢巴马亭对肝硬化门静脉高压和胰高糖素的影响．徐州医学院学报，1995，15(1)：9～11．
[142] 罗东，代青，管明银．速效枣仁安神胶囊中左旋延胡索乙素的定性鉴别及含量测定．药学实践杂志，1999，17(4)：233～235．
[143] 李丽清，杨敏丽，封满良，吕九如．流动注射化学发光法测定罗通定中延胡索乙素．分析化学，1997，25(11)：1321～1323．
[144] 张金凤，谭力，周继红，陆晓和，袁倚盛．HPLC测定人血浆中罗痛定浓度及药代动力学研究．中国药科大学学报，1998，29(1)：67～70．
[145] 张文伟，余伯阳，彭娟．左旋四氢巴马亭生物转化为左旋紫堇达明的研究．药物生物技术，2003，10(3)：165～168．
[146] 宣建成，林光大，金国章等．4种四氢原小檗碱同类物的立体结构和量子化学对多巴胺受体的作用关系．中国药理学报，1988，9(3)：197～205．
[147] 于治国，侯晓虹，时雅曼，马俊凤，毕开顺．HPLC测定吴茱萸及制剂中吴茱萸碱和吴茱萸次碱含量．中国药学杂志，1999，34(10)：691～693．
[148] 甄攀，杨凤珍．吴茱萸总生物碱提取条件的研究．分析仪器，2000，2：27～29．
[149] 宋建徽，孟祥琴，苏素文，郭鸣放，王川，苗庆峰，任雷鸣．安胃降逆饮对大鼠胃功能的影响．河北医科大学学报，2000，21(4)：202～204．
[150] 张虎，杨秀伟，崔育新．吴茱萸碱吴茱萸次碱和去氢吴茱萸碱的碳氢NMR信号全指定．波谱学杂志，1999，16(6)：563～567．
[151] 于德泉，杨俊山．《分析化学手册，核磁共振波谱分册》．北京：化学工业出版社，1999，690．
[152] 陈嬿，方圣鼎，磯具，彰铃木，昭惠．千金藤属植物小叶地不容中的生物碱(Ⅷ)．植物学报，1889，31(7)：544～548．
[153] Tetsuji K, keiichiro F, Masataka I, Akira U. Conformational analysis of the dibenzo[a,g]quinolizidines by spectroscopic methods. J. Org. Chem., 1975, 40 (22): 3280～3283.
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