连翘酯苷的吸收及代谢研究
|
摘要
连翘为木犀科植物连翘(Forsythia suspens (Thunb.) Vahl)的干燥果实。味苦性寒,具有清热解毒的功效,尤其对有病毒或细菌引起的上呼吸道感染有显著地疗效。连翘中所含苯乙醇类成分具有保护肝脏、消退黄疸的功效,其苷元咖啡酸及结构类似物绿原酸也均有护肝利胆作用。连翘酯苷(forsythiaside, FTA)属于苯乙醇苷类且是连翘的主要有效成分之一。FTA和连翘苷通常被作为连翘药材的主要质控及制备成分。文献报道,FTA在青翘和老翘中的含量分别4-7%和0.8-3%。近年来,对FTA的药理作用的研究中,发现其具有抗菌、抗病毒、抗氧化以及松弛血管等生物活性,但对FTA的药代动力学研究甚少。本论文采用高灵敏度的LC-MS/MS技术,以整体实验动物和体外细胞模型研究给予连翘酯苷后的药代动力学特性,包括其原型药物成分的吸收及代谢产物的测定。阐释FTA的药代动力学过程和规律。
首先,本文首次建立了高效、灵敏、稳定可靠地LC-MS/MS分析方法测定FTA在大鼠血浆中的含量。本方法选用表儿茶精作为内标物,并采用固相萃取法作为样品前处理方法。结果显示,FTA在大鼠血浆中的浓度在2.0～50.0和50.0～5000.0ng/mL范围内呈现良好的线性,并且此方法的最低检测限和最低定量限分别为0.2和1 ng／mL。同时呈现出了良好的精密度(RSD<10.8)和准确度>91.9%,且提取回收率在81.3%～85.0%之间,均达到生物样品测定方法学的要求。
其次,本文首次应用已经建立的LC-MS／MS分析方法,研究了FTA在大鼠体内的药代动力学特性。体内药代动力学结果表明大鼠口服FTA(100 mg／kg)后,达峰时间非常短(Tmax,20min),但其最大血药浓度低(Cmax,122.2±45.4 ng／mL),并且在体内消除快,静脉和口服FTA后其t1／2,λz分别为76.8±26.5 min及74.7±13.3 min,其AUCo-t分别为570.5±69.2μg min／mL及13.9±5.2μg min／mL。研究表明FTA的生物利用度很低,仅为0.5%。FTA机体稳定性的研究结果显示大鼠胃内容物对FTA无明显影响,而在小肠和大肠内容物中FTA均有不同程度的降解,其中在大肠内容物中降解最为明显,其降解率为38.7%。并且在FTApH环境稳定性研究中发现FTA在酸性下稳定,而在弱碱性和碱性条件易降解,从而表明在血浆和大肠中pH环境是引起FTA稳定性下降的主要因素。
再次,本文首次建立了体外Caco-2细胞模型,并以此模型对FTA在人体肠壁吸收机理进行研究,结果显示：FTA透膜能力差,其表观渗透系数(Papp)仅为1.2×10-7cm／s,属于吸收不良的药物,在Caco-2细胞模型上,不同浓度的FTA从AP→BL面和BL→AP面的Papp值无统计学差异,且其Papp值不会受药物浓度的增加而改变而转运量却会随浓度的增加而增加。综上所示,FTA在Caco-2单层细胞模型上,主要的转运方式为被动细胞转运。
第三,本文首次对FTA的排泄途径进行了研究。研究结果显示,在静脉给予大鼠FTA(20 mg／kg)后,经过11 h,尿液中累积排泄率为给药量的12.7±4.6%,而在胆汁中经过3 h的累积排泄率为给药量的1.36±0.31%。结果表明,FTA从胆汁和尿液中原型的排泄量约占给药量的15%,而其余药物可能转化为代谢物形式排出。
最后,本文首次研究了FTA的代谢途径,结果显示FTA在胆汁中拥有较强的代谢,利用LC-MS／MS中TIC模式和Product Ion模式鉴定出二相代谢物10种经LC-MS分析,与空白样品对比,在静脉给药后大鼠的尿样和胆汁中找到了FTA原型及其10种代谢物,分别为FTA单甲基化产物M1(m/z 637)；FTA双甲基化产物M2(m／z651)；FTA甲基化和硫酸化代谢物M3、M4(m／z 717、731)以及M3、M4的还原产物M5、M6(m／z 719、733)；FTA甲基化和葡萄糖醛酸化产物M7、M8(m／z 813、827)以及M7、M8的还原产物M9、M10(m／z 815、829)。
本论文研究结果系统的揭示了FTA吸收代谢规律,为苯乙醇苷类化合物的研究提供了实验依据,有利于正确评价此类药物的安全性与有效性,为此类药物的开发利用提供参考。
Forsythiaside (FTA), a phenylethanoid glycoside (Fig.1), is the most abundant component of a very well-known Chinese herbal medicine Lian-Qiao, which is the fruit of Forsythia suspense (Thunb) Vahl. The herb has been widely used as an antipyretic, antidotal and anti-inflammatory agent in China, Japan and Korea for the treatment of various infections, especially acute upper respiratory tract complaints caused by viruses and/or bacteria infection.FTA together with phillyrin are commonly used as chemical markers for quality control of Lian-Qiao raw material and the derivated preparations . The content of forsythiaside is about 4-7% in its dry green fruits named Qing-Qiao and 0.8-3%in its ripe fruits named Lao-Qiao Pharmacological studies demonstrated that FTA possesses strong antioxidant , antibacterial and antiviral activities, and also exhibits a slow relaxation effect against norepinephrine induced contraction of rat aorta.Moreover, it is reported that FTA could significantly protect DNA damage caused by hydroxyl radicals and inhibit protein kinase C (PKCa) with an IC50 value of 1.9μM. However, the pharmacokinetic characteristics and absorption profile in the gastrointestinal tract of FTA are largely unknown so far, due to lack of sensitive assays.
Firstly, a highly sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of FTA in rat plasma using epicatechin as internal standard. The analytes were extracted by solid-phase extraction and chromatographied on a C18 column eluted with a gradient mobile phase of acetonitrile and water both containing 0.2% formic acid. The detection was performed by negative ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 623→161 and m/z 289→109 for FTA and I.S., respectively. The assay was linear over the concentration ranges of 2.0-50.0 and 50.0-5000.0 ng/mL with limits of detection and quantification of 0.2 and 1.0 ng/mL, respectively. The precision was <10.8%and the accuracy was>91.9%, and extraction recovery ranged from 81.3%to 85.0%.
Secondly, a highly selective LC-MS/MS method has developed for quantificaiton of FTA in rat plasma to understand the pharmacokinetics and oral bioavailability of FTA in rats. And the results presented the absoption of FTA was extremely fast in rats (Tmax, 20 min) after intragastric admimistratiaon (100 mg/kg). However, the plasma concentration maximum was very low (Cmax,122.2±45.4 ng/mL). The elimination was fast after both intraveneous and intragastric administration (t1/2,λz 76.8±26.5 and 74.7±13.3 min). And the AUC0-t for intraveneous and intragastric administration were 570.5±69.2 and 13.9±5.2μg min/mL. All the pharmacokinetic parameters demonstrated the bioavailability of FTA in rat was very low in this study, just about 0.5%.
Thirdly, stability of FTA by peptidases was investigated by in cubation of the drug with different pH condition, the contents of stomach, small intestine, colon and plasma at 37℃.It showed that at pH 1.2 and pH 6.8, FTA was stable with no significant degradation for which is unstable at pH 7.4. Furthermore, FTA was stable in the stomach while unstable in the small intestine and colon. And after 4h incubation with their contents, FTA were degradated with 21%decrease in small intestine and 39%in colon, respectively. Compared with the two results, it presented that the degradation caused by the chemical (pH) instabilities in colon and plasma can not be ignored. Moreover the bacteria or enzymes in small intestine and colon played an important role in the degradation of FTA.
Moreover, In the Caco-2 cell model, the absorption transport of FTA was fairly poor with Papp values of 1.2×10-7cm/s. The bidirectional studies were performed under non-gradient conditions at a concentration of 100-300μM. Transport of FTA was not changed by the different concentrations. So, transport route of FTA was the passive transport.
Finally, the metabolites of FTA in urine and bile was determined by the LC-MS/MS. The intact form of FTA in the body was mainly excreted from urine at 12.7±4.6%of dose, and slightly excreted from bile at 1.4±0.3%of dose. FTA was extensively transferred into its methylated, sulfated or/and glucuronidated metabolites and then excreted from both urine and bile. The main metabolites of forsythiaside were characterized as its monomethylated metabolite Ml at m/z 637; bimethylated metabolite M2 at m/z 651; both methylated and sulfated metabolites M3 and M4 at m/z 717,731 and their reduced products M5 and M6 at m/z 719,733; both methylated and glucuronidated metabolites M7 and M8 at m/z 813,827 and their reduced products M9 and M10 at m/z 815,829.
首先,本文首次建立了高效、灵敏、稳定可靠地LC-MS/MS分析方法测定FTA在大鼠血浆中的含量。本方法选用表儿茶精作为内标物,并采用固相萃取法作为样品前处理方法。结果显示,FTA在大鼠血浆中的浓度在2.0～50.0和50.0～5000.0ng/mL范围内呈现良好的线性,并且此方法的最低检测限和最低定量限分别为0.2和1 ng／mL。同时呈现出了良好的精密度(RSD<10.8)和准确度>91.9%,且提取回收率在81.3%～85.0%之间,均达到生物样品测定方法学的要求。
其次,本文首次应用已经建立的LC-MS／MS分析方法,研究了FTA在大鼠体内的药代动力学特性。体内药代动力学结果表明大鼠口服FTA(100 mg／kg)后,达峰时间非常短(Tmax,20min),但其最大血药浓度低(Cmax,122.2±45.4 ng／mL),并且在体内消除快,静脉和口服FTA后其t1／2,λz分别为76.8±26.5 min及74.7±13.3 min,其AUCo-t分别为570.5±69.2μg min／mL及13.9±5.2μg min／mL。研究表明FTA的生物利用度很低,仅为0.5%。FTA机体稳定性的研究结果显示大鼠胃内容物对FTA无明显影响,而在小肠和大肠内容物中FTA均有不同程度的降解,其中在大肠内容物中降解最为明显,其降解率为38.7%。并且在FTApH环境稳定性研究中发现FTA在酸性下稳定,而在弱碱性和碱性条件易降解,从而表明在血浆和大肠中pH环境是引起FTA稳定性下降的主要因素。
再次,本文首次建立了体外Caco-2细胞模型,并以此模型对FTA在人体肠壁吸收机理进行研究,结果显示：FTA透膜能力差,其表观渗透系数(Papp)仅为1.2×10-7cm／s,属于吸收不良的药物,在Caco-2细胞模型上,不同浓度的FTA从AP→BL面和BL→AP面的Papp值无统计学差异,且其Papp值不会受药物浓度的增加而改变而转运量却会随浓度的增加而增加。综上所示,FTA在Caco-2单层细胞模型上,主要的转运方式为被动细胞转运。
第三,本文首次对FTA的排泄途径进行了研究。研究结果显示,在静脉给予大鼠FTA(20 mg／kg)后,经过11 h,尿液中累积排泄率为给药量的12.7±4.6%,而在胆汁中经过3 h的累积排泄率为给药量的1.36±0.31%。结果表明,FTA从胆汁和尿液中原型的排泄量约占给药量的15%,而其余药物可能转化为代谢物形式排出。
最后,本文首次研究了FTA的代谢途径,结果显示FTA在胆汁中拥有较强的代谢,利用LC-MS／MS中TIC模式和Product Ion模式鉴定出二相代谢物10种经LC-MS分析,与空白样品对比,在静脉给药后大鼠的尿样和胆汁中找到了FTA原型及其10种代谢物,分别为FTA单甲基化产物M1(m/z 637)；FTA双甲基化产物M2(m／z651)；FTA甲基化和硫酸化代谢物M3、M4(m／z 717、731)以及M3、M4的还原产物M5、M6(m／z 719、733)；FTA甲基化和葡萄糖醛酸化产物M7、M8(m／z 813、827)以及M7、M8的还原产物M9、M10(m／z 815、829)。
本论文研究结果系统的揭示了FTA吸收代谢规律,为苯乙醇苷类化合物的研究提供了实验依据,有利于正确评价此类药物的安全性与有效性,为此类药物的开发利用提供参考。
Forsythiaside (FTA), a phenylethanoid glycoside (Fig.1), is the most abundant component of a very well-known Chinese herbal medicine Lian-Qiao, which is the fruit of Forsythia suspense (Thunb) Vahl. The herb has been widely used as an antipyretic, antidotal and anti-inflammatory agent in China, Japan and Korea for the treatment of various infections, especially acute upper respiratory tract complaints caused by viruses and/or bacteria infection.FTA together with phillyrin are commonly used as chemical markers for quality control of Lian-Qiao raw material and the derivated preparations . The content of forsythiaside is about 4-7% in its dry green fruits named Qing-Qiao and 0.8-3%in its ripe fruits named Lao-Qiao Pharmacological studies demonstrated that FTA possesses strong antioxidant , antibacterial and antiviral activities, and also exhibits a slow relaxation effect against norepinephrine induced contraction of rat aorta.Moreover, it is reported that FTA could significantly protect DNA damage caused by hydroxyl radicals and inhibit protein kinase C (PKCa) with an IC50 value of 1.9μM. However, the pharmacokinetic characteristics and absorption profile in the gastrointestinal tract of FTA are largely unknown so far, due to lack of sensitive assays.
Firstly, a highly sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of FTA in rat plasma using epicatechin as internal standard. The analytes were extracted by solid-phase extraction and chromatographied on a C18 column eluted with a gradient mobile phase of acetonitrile and water both containing 0.2% formic acid. The detection was performed by negative ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 623→161 and m/z 289→109 for FTA and I.S., respectively. The assay was linear over the concentration ranges of 2.0-50.0 and 50.0-5000.0 ng/mL with limits of detection and quantification of 0.2 and 1.0 ng/mL, respectively. The precision was <10.8%and the accuracy was>91.9%, and extraction recovery ranged from 81.3%to 85.0%.
Secondly, a highly selective LC-MS/MS method has developed for quantificaiton of FTA in rat plasma to understand the pharmacokinetics and oral bioavailability of FTA in rats. And the results presented the absoption of FTA was extremely fast in rats (Tmax, 20 min) after intragastric admimistratiaon (100 mg/kg). However, the plasma concentration maximum was very low (Cmax,122.2±45.4 ng/mL). The elimination was fast after both intraveneous and intragastric administration (t1/2,λz 76.8±26.5 and 74.7±13.3 min). And the AUC0-t for intraveneous and intragastric administration were 570.5±69.2 and 13.9±5.2μg min/mL. All the pharmacokinetic parameters demonstrated the bioavailability of FTA in rat was very low in this study, just about 0.5%.
Thirdly, stability of FTA by peptidases was investigated by in cubation of the drug with different pH condition, the contents of stomach, small intestine, colon and plasma at 37℃.It showed that at pH 1.2 and pH 6.8, FTA was stable with no significant degradation for which is unstable at pH 7.4. Furthermore, FTA was stable in the stomach while unstable in the small intestine and colon. And after 4h incubation with their contents, FTA were degradated with 21%decrease in small intestine and 39%in colon, respectively. Compared with the two results, it presented that the degradation caused by the chemical (pH) instabilities in colon and plasma can not be ignored. Moreover the bacteria or enzymes in small intestine and colon played an important role in the degradation of FTA.
Moreover, In the Caco-2 cell model, the absorption transport of FTA was fairly poor with Papp values of 1.2×10-7cm/s. The bidirectional studies were performed under non-gradient conditions at a concentration of 100-300μM. Transport of FTA was not changed by the different concentrations. So, transport route of FTA was the passive transport.
Finally, the metabolites of FTA in urine and bile was determined by the LC-MS/MS. The intact form of FTA in the body was mainly excreted from urine at 12.7±4.6%of dose, and slightly excreted from bile at 1.4±0.3%of dose. FTA was extensively transferred into its methylated, sulfated or/and glucuronidated metabolites and then excreted from both urine and bile. The main metabolites of forsythiaside were characterized as its monomethylated metabolite Ml at m/z 637; bimethylated metabolite M2 at m/z 651; both methylated and sulfated metabolites M3 and M4 at m/z 717,731 and their reduced products M5 and M6 at m/z 719,733; both methylated and glucuronidated metabolites M7 and M8 at m/z 813,827 and their reduced products M9 and M10 at m/z 815,829.
引文
[1]Gao Hui-min, Wang Zhi-min,Wang Jia-min. Studies on Chemical Constituents in Stem ofAkebia trifoliatavar·australi [J], Zhong Guo Yao Xue Za Zhi,2006,41(5):333
[2]Chi Feng, Deng Jun, Wang Yanhan. A new phenylethanoid glucoside fromLagotis brevituba [J], Zhong Guo Zhong Yao Za Zhi,2009,34(16):2054
[3]Yang Li-juan,Yang Xiao-dong, Zhao Jing-feng, Li Liang. Studies on the Chem icalConstituents ofLagotis yunnanensis (Ⅱ) [J], Zhong Yao Cai,2006,29(2):128
[4]Li Li, Liu Zhi-Qiang, Liu Chun-Ming, Tsao Rong3, Lv Lei, Liu Shu-Ying. Studies on Phenylethanoid G lycosides in PlantExtract of Plantago asiaticalby Electrospray Ionization Multi-stage Tandem M ass Spectrometry [J], Gao Deng Xue Xiao Hua Xue Xue Bao,2006,27(8):1430
[5]Dan-Fei Huang, Yong-Fu Tang, Shao-Ping Nie, Yin Wan, Ming-Yong Xie, Xiao-Mei Xie. Effect of phenylethanoid glycosides and polysaccharides from the seed of Plantago asiatica L. on the maturation of murine bone marrow-derived dendritic cells[J], Eur J Pharmacol.,2009,620(1-3):105
[6]Li You-bin, Li Jun, Li Ping, Tu Peng-fei. Isolation and characterization of phenyle-thanoid glycosides from Clerodendron bungei[J], Yao Xue Xue Bao,2005,40(8):722
[7]Wang Yu-lan, Luan Xin. Phenethyl alcohol glycosides in Epimeredi indica[J]. Zhong CaoYao,2004,35(12):1325
[8]Wang Man-yuan, Yang Lan, Tu You-you. Phenylethanoid glycosides from stem of Chirita longgangensis var·hongyao[J], Zhong Guo Zhong Yao Za Zhi,2005,30(24):1921
[9]Chakravarty AK. Sarkar T, Nakane T, Kawahara N, Masuda K. New phenylethanoid glycosides from Bacopa monniera[J], Chem. Pharm. Bull,2002,50(12):1616
[10]Hou C C. Lin SJ, Cheng JT, Hsu FL. Bacopaside III, bacopasaponin G, and bacopasides A, B, and C from Bacopa monniera[J]. J. Nat Prod.2002,65(12):1759
[11]Xin Fei, Jin Yishu, Sha Yi, Xu Wei, Zhu Zheng, Li Yushan. Study on the Chemical Constituents of Verbena Officinalis[J]. Zhong Guo Xian Dai Zhong Yao.2008,10(10):21
[12]Han Peng, Cui Ya-jun, Guo Hong-zhu, Guo De-an. Chemical constituents of Buddlejae officinalis and their bioactivities[J].2004,35(10):1086
[13]Bui Huu TAI, Bong Yong JUNG, Nguyen Manh CUONG, Pham Thuy LINH, Nguyen Huu TUNG, Nguyen Xuan NHIEM, Tran Thu HUONG, Ngo Thi ANH, Jeong Ah KIM,Sang Kyum KIM, Young Ho KIM. Total Peroxynitrite Scavenging Capacity of Phenylethanoid and Flavonoid Glycosides from the Flowers of Buddleja officinalis[J]. Biol. Pharm. Bull.2009,32(12):1952
[14]Kuang Hai-Xue, Xia Yong-Gang,Yang Bing-You, Liang Jun, Zhang Qing-Bo, Li Guo-Yu. A New Caffeoyl Phenylethanoid Glycoside from the Unripe Fruits of Forsythia suspense[J]. Zhong Guo Tian Ran Yao Wu.2009,7(4):0278
[15]Li Li, Liu Chun-ming, Liu Zhi qiang, Lv Leil, Liu Shu-ying, Extraction and ESI2MSn Studies of Phenylethanoid Glycosides in Cistanche deserticola[J]. Zhi Pu Xue Bao.2006,27(4):232
[16]Wang Yi-ming, Zhang Si-ju, Luo Guo-an, Hu Ya-nan. Analysis of Phenylethan-oid Glycosides in the Extract of HerbaCistanchisby LC/ESI-MS/MS[J]. Yao Xue Xue Bao.2000,35(11):839
[17]Zheng Xiao-ke, Li Jun, Feng Wei-sheng, Bi Yue-feng, Ji Chun-ru. Studies on phenylethanoid glycosides fromCorallodiscus flabellate[J]. Zhong Cao Yao. 2002,33(10):881
[18]Jiang Hong-Liang, Xu Li-zhen, Yang Xue-dong, Zhang Da, Yang Shi-lin, Zou Zhong-mei. Quinic Acid Esters from Herba of Siphonostegia chinensis[J]. Zhong Guo Zhong Yao Za Zhi.2002,27(12):926
[19]Zheng Xiao-ke, Li Jun, Feng Wei-sheng, Bi Yue-feng, Ji Chun-ru. Isolation and structural identification of phenylethanoid glycosides fromCorallodiscusflabellata[J]. Yao Xue Xue Bao.2003,38(2):116
[20]Zheng Xiao-ke, Liu Yun-bao, Li Jun, Feng Wei-sheng. One new phenylethanoid glycoside from Corallodiscus flabellate[J]. Yao Xue Xue Bao.2004,39(9):716
[21]Chen Yu-juan, Wang Hui-tang, He Li-peng, Zhang Hong-gui, Yin Jin-ling. Study on Chemical Constituents from Bark of Fraxinus mandschurica Rupr.[J]. Zhong Guo Yao Xue Za Zhi.2009,44(15):1133
[22]Liu Pu, Teng Jie, Zhang Yan-wen, TAKAISHI Yoshihisa, Duan Hong-qua. Chem ical constituents from rhizome of Phlomis umbrosa[J]. Yao Xue Xue Bao. 2007,42(4):401
[23]Huang Kai-yi, He Lei, QU Yang, Gao Hui-yuan, Deng Xu-ming, Wu Li-ju. Isolation and identification of chem ical constituents from roots of Picrorhiza Scrophulariiflora Pennel[J]. Shen Yang Yao Ke Da Xue Xue Bao.2009,26(2):112
[24]Toshio MORIKAWA, Bohang SUN, Hisashi MATSUDA, Li Jun WU, Shoichi HARIMA, Masayuki YOSHIKAWA. Bioactive Constituents from Chinese Natural Medicines. XIV.1) New Glycosides of β-Carboline-Type Alkaloid, Neolignan, and Phenylpropanoid from Stellaria dichotoma L. var. lanceolata and Their Antiallergic Activities. Chem. Pharm. Bull.2004,52(10):1194
[25]ALBERTO PLAZA, PAOLA MONTORO, ANGELYNE BENAVIDES, COSIMO PIZZA, SONIA PIACENTE. Phenylpropanoid Glycosides from Tynanthus panurensis:Characterization and LC-MS Quantitative Analysis[J]. J. Agric. Food Chem. 2005,53(8):2853
[26]M. Mostafa, Nasim Sultana, Nilufar Nahar, M. Mosihuzzaman, M. Iqbal Choudhary. A new phenylpropanoid glycoside from Leucas indica Linn[J]. J. Nat. Prod. Res. 2009,11(1):29
[27]Miao Ye, Yun Zhao, Vanessa L. Norman, Courtney M. Starks, Stephanie M. Rice, Matt G. Goering, Mark O'Neil-Johnson, Gary R. Eldridge, Jin-Feng Hu. Antibiofilm Phenylethanoid Glycosides from Penstemon centranthifolius[J]. Phytother. Res.2010, 24(5):778
[28]Severina Pacifico, Brigida D'Abrosca, Maria Teresa Pascarella, Marianna Letizia, Piera Uzzo, Vincenzo Piscopo, Antonio Fiorentino. Antioxidant efficacy of iridoid and phenylethanoid glycosides from the medicinal plant Teucrium chamaedris in cell-free systems[J]. Bioorganic & Medicinal Chemistry.2009,17:6173
[29]Fre'de'ric Martin, Anne-Emmanuelle Hay, Valentin R. Quinteros Condoretty, Delphine Cressend, Marianne Reist, Mahabir P. Gupta, Pierre-Alain Carrupt, Kurt Hostettmann. Antioxidant Phenylethanoid Glycosides and a Neolignan from Jacaranda caucana[J]. J. Nat. Prod.2009,72:852
[30]Nanoko ITO, Tamotsu NIHEI, Rie KAKUDA, Yasunori YAOITA, and Masao KIKUCHI. Five New Phenylethanoid Glycosides from the Whole Plants of Lamium purpureum L[J]. Chem. Pharm. Bull.2006,54(12):1705
[31]Rainer Gormann, Maki Kaloga, Daneel Ferreira, Jannie P.J. Marais, Herbert Kolodziej. Newbouldiosides A-C, phenylethanoid glycosides from the stem bark of Newbouldia laevis[J]. Phytochemistry.2006,67:805
[32]Jose'G Sena Filho, Susan L. Nimmo, Haroudo S. Xavier, Jose'M.Barbosa-Filho, Robert H. Cichewicz. Phenylethanoid and Lignan Glycosides from Polar Extracts of Lantana, a Genus of Verbenaceous Plants Widely Used in Traditional Herbal Therapies [J]. J.Nat. Prod.2009,72:1344
[33]Lisieux de Santana Juliao, Anna Lisa Piccinelli, Stefania Marzocco, Suzana Guimara-es Leitao, Cinzia Lotti, Giuseppina Autore, and Luca Rastrelli. Phenylethanoid Glycosides from Lantana fucata with in Vitro Anti-inflammatory Activity [J]. J. Nat. Prod. 2009,72:1424
[34]Pu Liua, Rui-Xue Denga, Hong-Quan Duanb, Wei-Ping Yina, Tian-Zeng Zhao. Phenylethanoid glycosides from the roots of Phlomis umbrosa[J]. J. Nat. Prod. Res. 2009,11(1):69
[35]Emanuela P. Kostadinova a, Kalina I. Alipieva a, Tetsuo Kokubun b, Rilka M. Taskova c, Nedjalka V. Handjieva. Phenylethanoids, iridoids and a spirostanol saponin from Veronica turrilliana[J]. Phytochemistry,2007,68:1321
[36]Lidilhone Hamerski, Mauro Dionei Bomm, Dulce Helena Siqueira Silva, Maria Cla 'udia Marx Young, Maysa Furlan, Marcos Nogueira Eberlin, Ian Castro-Gamboa, Alberto Jose'Cavalheiro, Vanderlan da Silva Bolzani. Phenylpropanoid glucosides from leaves of Coussarea hydrangeifolia (Rubiaceae)[J]. Phytochemistry,2005,66:1927
[37]Ying Chen, Xin-Min Liu, Rui-Le Pan, Geng-Nan Wang, Ying Fu, Qi Chang:A LC-MS/MS method for determination of 3,6'-disinapoylsucrose in rat plasma and its application in a pharmacokinetic study [J]. Biomedical Chromatography. 2009,23(12):1326
[38]冯淑怡,李先荣,孙建宁.连翘酯苷抗感染、解热作用研究. 现代生物医学进展[J].2006,6(10)：73
[39]李教社,赵玉英.密蒙花中苯乙醇苷的分离和鉴定[J].中国中药杂志,1997,12(7)：613
[40]M. Hausmann, F. Obermeier, D. H. Paper, et al. In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis [J]. Clinical and Experimental Immunology,2007,148:373-381
[41]Elfrides E. S. Schapoval, Mara R. Winter de Vargas。Celia G. ChaYeS, et al. Antiinflammatory and antinociceptive activities of extracts and isolated compounds from Stachytarpheta cayannensis [J]. Journal of Ethnopharmacology.1998,60:53
[42]Shigetoshi KADOTA, et al. Antioxidative Efects of Phenylethanolds from Cistanehe deseticola [J]. Biol. Pharm. Bull.1996,19(12):1580
[43]Sasaki H, Nishimura H, Morota T, et al. Immunosuppressive pfinciples of Rehmannia glutinosa var hueichingensis[J]. Planta Med,1989,55(5):458.
[44]Dang-Lei Liu, yang Zhang, Sui-Xu Xu, et al. Phenylethanoid glycosides from Forsythia suspense Vabl [J]. Journal of Chinese Pharmaceutical Sciences.1998,7(2):103
[45]Hao WANG, Yang SUN, Wen-Cai YE, et al. Antioxidative Phenylethanoid and Phenolic Glycosides from Picrorhiza scrophulariiflora[J]. Chem. Pharm. Bull,2004, 52(5):615
[46]Ivan Yuen Fan Wong, Zheng—Dan He, Yu Huang, et al. Antioxidative Activities of Phenylethanoid Glycosides from Ligustrum purpurascens[J]. J. Asrlc Food Chem, 2001,49(6):3113
[47]康旭珍.连翘酯苷抗氧化活性研究.中华综合临床医学杂志[J],2005,7(9)：7]0
[48]陈瑞川,苏金华,蔡克瑕,等.天然抗氧化剂Isoverbascoside诱导人胃癌MGC803细胞分化作用研究[J].厦门大学学报(自然科学版),2001,40(4)：936
[49]Takamasa OHNO, Makoto INOUE, Yukio OGIHARA, et al. Antimetastatic Activity of Acteoside, a Phenylethanoid Glycoside[J]. Biol. Pharm. Bull,2002,25(5):666
[50]Fumiko ABE, Tsuneatsu NAGAO, Hikaru OKABE. Antiproliferative Constituents in Plants 9. Aerial Parts of Lippia dulcis and Lippia canescens[J]. Biol. Pharm. Bull,2002,25(7):920
[51]邓敏,赵金垣,屠鹏飞,等.松果菊苷对TNFa诱导的SH-SY5Y细胞凋亡的保护作用[J].中国药理学通报,2005,21(2)：169
[52]Chi-Wai Lau,Zhen-Yu Chen,Chi-Ming Wong, et al. Attenuated endothelium-mediated relaxation by acteoside in rat aorta:Role of endothelial [Ca2+]i and nitric oxide/cyclic GMP pathway[J]. Life Sciences,2004,75:1149
[53]Marcello Pennacchio, Elizabeth Alexander, Yana M. Syah, et al. The efect of verbascoside on cyclic 3,5-adenosine monophosphate levels in isolated rat heart[J]. European Journal Pharmacology,1996,305:169
[54]Ki Yong LEE, Eun Ju JEONG, Heum-Sook LEE, et al. Acteoside of Callicarpa dichotoma Attenuates Scopolamine-Induced Memory Impairments[J]. Biol Pharm. Bull, 2006,29(1):71
[55]田枫,张阔,康爱君,等.松果菊苷改善SAM—P／8小鼠学习记忆能力作用机制初探[J].实验动物科学与管理,2006,23(2)：14
[56]赵欣,蒲小平,耿兴超.松果菊苷对帕金森病模型小鼠黑质纹状体蛋白表达影响的双向电泳分析[J].中国药理学通报,2008,24(1)：28
[57]Hisashi Matsuda, Toshio Morikawa, Hiromi Managi, et al. Antiallergic Principles from Alpinia galanga:Structural Requirements of Phenylpropanoids for Inhibition of Degranulation and Release of TNF-a and IL-4 in RBL-2H3 Cells[J]. Bioorganic & Medicinal Chemistry Letters.2003,13:3197
[58]Kyung Ah Koo, Seung Hyun Kim, Tae Hwan Oh, et al. Acteoside and its aglycones protect primary cultures of rat cortical cells from glutamate-induced excitotoxicity[J]. Life Sciences,2006,79:709
[59]Cunqin Jia, Haiming Shi, Xiangmei Wu, et al. Determination of echinacoside in rat serum by reversed-phase high-performance liquid chromatography with ultraviolet detection and its application to pharmacokinetics and bioavailability[J]. Journal of Chromatography B,2006,844:308
[60]A.Matthias, J.T. Blanchfield, K.G. Penman, I. Toch, C.S.Lang, J.J. De Voss, R.P. Lehmann, J. Clin. Pharm. Therapeut,2004,29:7
[61]A.Matthias, R.S. Addison, K.G Penman, R.G Dickinson, K.M. Bone, R.P. Lehmann. Life Sci,2005,77:2018
[62]A.Matthias, K.G. Penman, N.J. Matovic, K.M. Bone, J.J. De Voss, R.P. Lehmann, Molecules,2005,10:1242
[63]Cunqin Jia, Haiming Shi, Wei Jin, Ke Zhang, Yong Jiang, Mingbo Zhao, and Pengfei Tu. Metabolism of Echinacoside, a Good Antioxidant, in Rats:Isolation and Identification of Its Biliary Metabolites[J]. Drug Metabolism and disposition,2009, 37(2):431
[64]Yu-Tse Wu, Lie-Chwen Lin, Jung-Sung Sung, et al. Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely-moving rats using LC-MS/MS[J]. Journal of Chromatography B,2006,844:89
[65]雷厉,宋志宏,李寅增,等.管花肉苁蓉苯乙醇总苷在狗胃肠道内的生物转化[J].药学学报,2001,36(6)：432
[66]Yun-Xia Li, Xue-Hua Jiang, Hu-Yi Liang, et al. Determination of forsythiaside in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies[J]. Biomed. Chromatogr.2007,10:1002
[67]陈颖,远志活性成分的吸收和代谢研究。协和医科大学博士论文,2009
[1]X.L. Piao, E.J. Cho, M.H. Jang, J. Cui, Cytoprotective effect of lignans from Forsythia suspensa against peroxynitrite-induced LLC-PK1 cell damage[J]. Phytother. Res.,2009,23(7):938-942
[2]J. Han, M. Ye, H. Guo, M. Yang, B.R. Wang, D.A. Guo, Analysis of multiple constituents in a Chinese herbal preparation Shuang-Huang-Lian oral liquid by HPLC-DAD-ESI-MSn. J. Pharmaceut. Biomed. Anal.2007,44(2):430-438.
[3]Y.Y. Cui, S.Y. Feng, G. Zhao, M.Z. Wang, HPLC analysis of the active ingredients of Forsythia suspense[J]. Yao Xue Xue Bao.1992,27(8):603-608
[4]H.H. Qu, X.F. Zhai, B.X. Li, W.J. Sun, Study of the content of forsythiaside and forsythin from different parts of Forsythia suspensa(Thunb.)Vahl[J]. Yao Wu Fen Xi Za Zhi,2008,28(3):382-385
[5]D. Wang, Y.Y. Zhou, J. Harbin Univ. Commerce (Nat. Sci. Ed.) 2004,20:462
[6]W.H. Zhao, R.B. Shi, B. Liu, L.Z. Zhang, Determination of phillyrin and forsythoside A in Lianqiao Bingdu Qing capsule by RP-HPLC[J]. Zhongguo Zhong Yao Za Zhi,2005,30(1):36-39
[7]张炜,张汉明,郭美丽,杨继斌,朱美玲,HPLC法测定感冒退热颗粒(冲剂)中连翘酯苷A的含量。中草药,1999,30(4)：268-270
[8]H. Qu, Y. Zhang, Y. Wang, B. Li, W. Sun, Antioxidant and antibacterial activity of two compounds (forsythiaside and forsythin) isolated from Forsythia suspensa[J]. J. Pharm. Pharmacol.2008,60(2):261-266
[9]L.W. Zhang, C.G. Zhao, P. Yang, Study on the antioxidant activity and structure-activity relationship of forsythiaside [J]. Zhong Guo Yao Xue Za Zhi,2003, 38(5):334-336
[10]H.C. Ko, B.L. Wei, W.F. Chiou, Dual regulatory effect of plant extracts of Forsythia suspense on RANTES and MCP-1 secretion in influenza A virus-infected human bronchial epithelial cells[J]. J. Ethnopharmacol.2005,102(3):418-423
[11]胡克杰,徐凯建,王跃红,孙考祥,王栋,连翘酯甙体外抗病毒作用的实验研究[J]。 中国中医药科技,2001,8：89
[12]T. Iizuka, M. Nagai, Vasorelaxant effects of forsythiaside from the fruits of Forsythia suspense[J]. Yakugaku Zasshi,2005,125(2):219-224
[13]J. Liu, L.W. Zhang, Functions of Forsythiaside on the Damage of DNA Induced by Hydroxyl Radical[J]. Shanxi Zhong Yi Xue Yuan Xue Bao,2006,7(1):23-24
[14]B.N. Zhou, B.D. Bahler, G.A. Hofmann, M.R. Mattern, R.K. Johnson, D.G.I. Kingston, Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity[J]. J. Nat. Prod.,1998,61(11):1410-1412
[15]Y.X. Li, X.H. Jiang, H.Y. Liang, X. Li, Determination of forsythiaside in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies[J]. Biomed. Chromatogr.2008,22(4):361
[16]J.D. Wang, Q.Y. Chai, L.W. Zhang, Pharmacokinetics of Forsythiasie in Rats[J]. Shijie Kexue Jishu-Zhong Yi Yao Xian Dai Hua.2008,10(4):53-57
[17]R. Shi, Z. Xuan, Y. Ma, Y. Liu, H. Lu, T. Sun, Pharmacokinetics of forsythoside after intravenous administration in beagle dogs[J]. Eur. J. Drug Metab.Pharmacokinet. 2009,34(2):101-105
[18]Y.X. Li, C. Peng, R.Q. Zhang, X. Li, X.H. Jiang, Pharmacokinetics of phillyrin and forsythiaside following iv administration to Beagle dog [J].Eur. J. Drug Metab. Pharmacokinet.2009,34(2):79-83
[19]S.M. Dong, Q.Y. De. J. Asia Nat. Prod Res,1999,1:327
[20]L. W. Zhang, P. Study on the stability of forsythiasid[J]. Yang. Zhong Cheng Yao, 2003,25(5):353-356
[21]C.Q. Jia, H.M. Shi, W. Jin, K. Zhang, Y. Jiang, M.B. Zhao, P.F. Tu. Metabolism of echinacoside, a good antioxidant, in rats:isolation and identification of its biliary metabolites [J]. Drug Metab. Dispos.,2009,37(2):431-438
[22]Y.T. Wu, L.C. Lin, J.S. Sung, T.H. Tsai. Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely-moving rats using LC-MS/MS[J]. J. Chromatogr. B,2006,844:89-95
[23]Y. Chen, X.M. Liu, R.L. Pan, G.N. Wang, Y. Fu, Q. Chang. An LC-MS/MS method for determination of 3,6'-disinapoylsucrose in rat plasma and its application to a pharmacokinetic study[J]. Biomed. Chromatogr.,2009,23(12):1326-1332
[24]Okada T, Naraia, A, Matsunage S, Fusetani N, Shkimizu M. Assessment of the marine toxins by monitoring the integrity of human intestinal Caco-2 cell monolayers [J]. Toxicol In Vitro,2000,14(3):219-226
[25]Aiba T, Ishida K, Yoshinaga M, et al. Pharmacokinetic characterization of transcellular transport and drug interaction of digoxin in Caco-2 cell monolayers [J]. Biol Pharm Bull,2005,28(1):114-119
[26]Konsoula R, Bar Ilefa. Correlation of in vitro cytotoxicity with paracellular permeability in Caco-2 cells [J]. Toxicol In Vitro,2005,19(5):675-684
[27]Gresm C, Julian B, Bourrie M, et al. Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line:comparison with the parental Caco-2 cell line[J]. Pharm Res,1998,15(5):726-733
[28]Yee S Y. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997,14 (6):763-766
[29]Jung S J, Choi S O, Uma S Y. Prediction of the permeability of drugs through study on quantitative structure-permeability relationship[J]. J Pharm Biomed Anal,2006, 41(2):469-475
[30]Asano T, Ish Ihara K, Morota T, et al. Permeability of the flavonoids liquiritigenin and its glycosides in licorice roots and davidigenin, a hydrogenated metabolite of liquiritigenin, using human intestinal cell line Caco-2[J]. J Ethnopharmacol,2003, 89(2-3):285-289
[31]Annaert P, Gelder JV, Naesens L, et al. Carrier mechanisms involved in the transepithelial transport of bis(POM)-PMEA and its metabolites across Caco-2 monolayers[J].Pharm Res,1998,15(8):1168-1173
[32]Walgren RA, Karnaky KJ, Lindenmayer GE, et al. Pharmcol Expther,2000,294: 830
[33]Makhey VD, Guo A, Norris DA, et al. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells[J]. Pharm Res, 1998,15(8):1160-1167
[34]R.L. Cai, M. Wang, Y. Qi, X.Y. Wang, C. Xie, X.Z. Luo, Selection and Utilization on the Evaluation Criterions of Caco-2 Cell Model [J]. Zhong Guo Yao Xue Za Zhi.2008,43(24):1871-1874
[35]屠锡德,张钧寿,朱家璧主编.药剂学.第3版.北京：人民卫生出版社,2002.1219
[36]R. JE. Iowa State University Press,1999.63
[37]梁文权,生物药剂学与药物动力学.第2版.北京：人民卫生出版社,2000.122
[2]Chi Feng, Deng Jun, Wang Yanhan. A new phenylethanoid glucoside fromLagotis brevituba [J], Zhong Guo Zhong Yao Za Zhi,2009,34(16):2054
[3]Yang Li-juan,Yang Xiao-dong, Zhao Jing-feng, Li Liang. Studies on the Chem icalConstituents ofLagotis yunnanensis (Ⅱ) [J], Zhong Yao Cai,2006,29(2):128
[4]Li Li, Liu Zhi-Qiang, Liu Chun-Ming, Tsao Rong3, Lv Lei, Liu Shu-Ying. Studies on Phenylethanoid G lycosides in PlantExtract of Plantago asiaticalby Electrospray Ionization Multi-stage Tandem M ass Spectrometry [J], Gao Deng Xue Xiao Hua Xue Xue Bao,2006,27(8):1430
[5]Dan-Fei Huang, Yong-Fu Tang, Shao-Ping Nie, Yin Wan, Ming-Yong Xie, Xiao-Mei Xie. Effect of phenylethanoid glycosides and polysaccharides from the seed of Plantago asiatica L. on the maturation of murine bone marrow-derived dendritic cells[J], Eur J Pharmacol.,2009,620(1-3):105
[6]Li You-bin, Li Jun, Li Ping, Tu Peng-fei. Isolation and characterization of phenyle-thanoid glycosides from Clerodendron bungei[J], Yao Xue Xue Bao,2005,40(8):722
[7]Wang Yu-lan, Luan Xin. Phenethyl alcohol glycosides in Epimeredi indica[J]. Zhong CaoYao,2004,35(12):1325
[8]Wang Man-yuan, Yang Lan, Tu You-you. Phenylethanoid glycosides from stem of Chirita longgangensis var·hongyao[J], Zhong Guo Zhong Yao Za Zhi,2005,30(24):1921
[9]Chakravarty AK. Sarkar T, Nakane T, Kawahara N, Masuda K. New phenylethanoid glycosides from Bacopa monniera[J], Chem. Pharm. Bull,2002,50(12):1616
[10]Hou C C. Lin SJ, Cheng JT, Hsu FL. Bacopaside III, bacopasaponin G, and bacopasides A, B, and C from Bacopa monniera[J]. J. Nat Prod.2002,65(12):1759
[11]Xin Fei, Jin Yishu, Sha Yi, Xu Wei, Zhu Zheng, Li Yushan. Study on the Chemical Constituents of Verbena Officinalis[J]. Zhong Guo Xian Dai Zhong Yao.2008,10(10):21
[12]Han Peng, Cui Ya-jun, Guo Hong-zhu, Guo De-an. Chemical constituents of Buddlejae officinalis and their bioactivities[J].2004,35(10):1086
[13]Bui Huu TAI, Bong Yong JUNG, Nguyen Manh CUONG, Pham Thuy LINH, Nguyen Huu TUNG, Nguyen Xuan NHIEM, Tran Thu HUONG, Ngo Thi ANH, Jeong Ah KIM,Sang Kyum KIM, Young Ho KIM. Total Peroxynitrite Scavenging Capacity of Phenylethanoid and Flavonoid Glycosides from the Flowers of Buddleja officinalis[J]. Biol. Pharm. Bull.2009,32(12):1952
[14]Kuang Hai-Xue, Xia Yong-Gang,Yang Bing-You, Liang Jun, Zhang Qing-Bo, Li Guo-Yu. A New Caffeoyl Phenylethanoid Glycoside from the Unripe Fruits of Forsythia suspense[J]. Zhong Guo Tian Ran Yao Wu.2009,7(4):0278
[15]Li Li, Liu Chun-ming, Liu Zhi qiang, Lv Leil, Liu Shu-ying, Extraction and ESI2MSn Studies of Phenylethanoid Glycosides in Cistanche deserticola[J]. Zhi Pu Xue Bao.2006,27(4):232
[16]Wang Yi-ming, Zhang Si-ju, Luo Guo-an, Hu Ya-nan. Analysis of Phenylethan-oid Glycosides in the Extract of HerbaCistanchisby LC/ESI-MS/MS[J]. Yao Xue Xue Bao.2000,35(11):839
[17]Zheng Xiao-ke, Li Jun, Feng Wei-sheng, Bi Yue-feng, Ji Chun-ru. Studies on phenylethanoid glycosides fromCorallodiscus flabellate[J]. Zhong Cao Yao. 2002,33(10):881
[18]Jiang Hong-Liang, Xu Li-zhen, Yang Xue-dong, Zhang Da, Yang Shi-lin, Zou Zhong-mei. Quinic Acid Esters from Herba of Siphonostegia chinensis[J]. Zhong Guo Zhong Yao Za Zhi.2002,27(12):926
[19]Zheng Xiao-ke, Li Jun, Feng Wei-sheng, Bi Yue-feng, Ji Chun-ru. Isolation and structural identification of phenylethanoid glycosides fromCorallodiscusflabellata[J]. Yao Xue Xue Bao.2003,38(2):116
[20]Zheng Xiao-ke, Liu Yun-bao, Li Jun, Feng Wei-sheng. One new phenylethanoid glycoside from Corallodiscus flabellate[J]. Yao Xue Xue Bao.2004,39(9):716
[21]Chen Yu-juan, Wang Hui-tang, He Li-peng, Zhang Hong-gui, Yin Jin-ling. Study on Chemical Constituents from Bark of Fraxinus mandschurica Rupr.[J]. Zhong Guo Yao Xue Za Zhi.2009,44(15):1133
[22]Liu Pu, Teng Jie, Zhang Yan-wen, TAKAISHI Yoshihisa, Duan Hong-qua. Chem ical constituents from rhizome of Phlomis umbrosa[J]. Yao Xue Xue Bao. 2007,42(4):401
[23]Huang Kai-yi, He Lei, QU Yang, Gao Hui-yuan, Deng Xu-ming, Wu Li-ju. Isolation and identification of chem ical constituents from roots of Picrorhiza Scrophulariiflora Pennel[J]. Shen Yang Yao Ke Da Xue Xue Bao.2009,26(2):112
[24]Toshio MORIKAWA, Bohang SUN, Hisashi MATSUDA, Li Jun WU, Shoichi HARIMA, Masayuki YOSHIKAWA. Bioactive Constituents from Chinese Natural Medicines. XIV.1) New Glycosides of β-Carboline-Type Alkaloid, Neolignan, and Phenylpropanoid from Stellaria dichotoma L. var. lanceolata and Their Antiallergic Activities. Chem. Pharm. Bull.2004,52(10):1194
[25]ALBERTO PLAZA, PAOLA MONTORO, ANGELYNE BENAVIDES, COSIMO PIZZA, SONIA PIACENTE. Phenylpropanoid Glycosides from Tynanthus panurensis:Characterization and LC-MS Quantitative Analysis[J]. J. Agric. Food Chem. 2005,53(8):2853
[26]M. Mostafa, Nasim Sultana, Nilufar Nahar, M. Mosihuzzaman, M. Iqbal Choudhary. A new phenylpropanoid glycoside from Leucas indica Linn[J]. J. Nat. Prod. Res. 2009,11(1):29
[27]Miao Ye, Yun Zhao, Vanessa L. Norman, Courtney M. Starks, Stephanie M. Rice, Matt G. Goering, Mark O'Neil-Johnson, Gary R. Eldridge, Jin-Feng Hu. Antibiofilm Phenylethanoid Glycosides from Penstemon centranthifolius[J]. Phytother. Res.2010, 24(5):778
[28]Severina Pacifico, Brigida D'Abrosca, Maria Teresa Pascarella, Marianna Letizia, Piera Uzzo, Vincenzo Piscopo, Antonio Fiorentino. Antioxidant efficacy of iridoid and phenylethanoid glycosides from the medicinal plant Teucrium chamaedris in cell-free systems[J]. Bioorganic & Medicinal Chemistry.2009,17:6173
[29]Fre'de'ric Martin, Anne-Emmanuelle Hay, Valentin R. Quinteros Condoretty, Delphine Cressend, Marianne Reist, Mahabir P. Gupta, Pierre-Alain Carrupt, Kurt Hostettmann. Antioxidant Phenylethanoid Glycosides and a Neolignan from Jacaranda caucana[J]. J. Nat. Prod.2009,72:852
[30]Nanoko ITO, Tamotsu NIHEI, Rie KAKUDA, Yasunori YAOITA, and Masao KIKUCHI. Five New Phenylethanoid Glycosides from the Whole Plants of Lamium purpureum L[J]. Chem. Pharm. Bull.2006,54(12):1705
[31]Rainer Gormann, Maki Kaloga, Daneel Ferreira, Jannie P.J. Marais, Herbert Kolodziej. Newbouldiosides A-C, phenylethanoid glycosides from the stem bark of Newbouldia laevis[J]. Phytochemistry.2006,67:805
[32]Jose'G Sena Filho, Susan L. Nimmo, Haroudo S. Xavier, Jose'M.Barbosa-Filho, Robert H. Cichewicz. Phenylethanoid and Lignan Glycosides from Polar Extracts of Lantana, a Genus of Verbenaceous Plants Widely Used in Traditional Herbal Therapies [J]. J.Nat. Prod.2009,72:1344
[33]Lisieux de Santana Juliao, Anna Lisa Piccinelli, Stefania Marzocco, Suzana Guimara-es Leitao, Cinzia Lotti, Giuseppina Autore, and Luca Rastrelli. Phenylethanoid Glycosides from Lantana fucata with in Vitro Anti-inflammatory Activity [J]. J. Nat. Prod. 2009,72:1424
[34]Pu Liua, Rui-Xue Denga, Hong-Quan Duanb, Wei-Ping Yina, Tian-Zeng Zhao. Phenylethanoid glycosides from the roots of Phlomis umbrosa[J]. J. Nat. Prod. Res. 2009,11(1):69
[35]Emanuela P. Kostadinova a, Kalina I. Alipieva a, Tetsuo Kokubun b, Rilka M. Taskova c, Nedjalka V. Handjieva. Phenylethanoids, iridoids and a spirostanol saponin from Veronica turrilliana[J]. Phytochemistry,2007,68:1321
[36]Lidilhone Hamerski, Mauro Dionei Bomm, Dulce Helena Siqueira Silva, Maria Cla 'udia Marx Young, Maysa Furlan, Marcos Nogueira Eberlin, Ian Castro-Gamboa, Alberto Jose'Cavalheiro, Vanderlan da Silva Bolzani. Phenylpropanoid glucosides from leaves of Coussarea hydrangeifolia (Rubiaceae)[J]. Phytochemistry,2005,66:1927
[37]Ying Chen, Xin-Min Liu, Rui-Le Pan, Geng-Nan Wang, Ying Fu, Qi Chang:A LC-MS/MS method for determination of 3,6'-disinapoylsucrose in rat plasma and its application in a pharmacokinetic study [J]. Biomedical Chromatography. 2009,23(12):1326
[38]冯淑怡,李先荣,孙建宁.连翘酯苷抗感染、解热作用研究. 现代生物医学进展[J].2006,6(10)：73
[39]李教社,赵玉英.密蒙花中苯乙醇苷的分离和鉴定[J].中国中药杂志,1997,12(7)：613
[40]M. Hausmann, F. Obermeier, D. H. Paper, et al. In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis [J]. Clinical and Experimental Immunology,2007,148:373-381
[41]Elfrides E. S. Schapoval, Mara R. Winter de Vargas。Celia G. ChaYeS, et al. Antiinflammatory and antinociceptive activities of extracts and isolated compounds from Stachytarpheta cayannensis [J]. Journal of Ethnopharmacology.1998,60:53
[42]Shigetoshi KADOTA, et al. Antioxidative Efects of Phenylethanolds from Cistanehe deseticola [J]. Biol. Pharm. Bull.1996,19(12):1580
[43]Sasaki H, Nishimura H, Morota T, et al. Immunosuppressive pfinciples of Rehmannia glutinosa var hueichingensis[J]. Planta Med,1989,55(5):458.
[44]Dang-Lei Liu, yang Zhang, Sui-Xu Xu, et al. Phenylethanoid glycosides from Forsythia suspense Vabl [J]. Journal of Chinese Pharmaceutical Sciences.1998,7(2):103
[45]Hao WANG, Yang SUN, Wen-Cai YE, et al. Antioxidative Phenylethanoid and Phenolic Glycosides from Picrorhiza scrophulariiflora[J]. Chem. Pharm. Bull,2004, 52(5):615
[46]Ivan Yuen Fan Wong, Zheng—Dan He, Yu Huang, et al. Antioxidative Activities of Phenylethanoid Glycosides from Ligustrum purpurascens[J]. J. Asrlc Food Chem, 2001,49(6):3113
[47]康旭珍.连翘酯苷抗氧化活性研究.中华综合临床医学杂志[J],2005,7(9)：7]0
[48]陈瑞川,苏金华,蔡克瑕,等.天然抗氧化剂Isoverbascoside诱导人胃癌MGC803细胞分化作用研究[J].厦门大学学报(自然科学版),2001,40(4)：936
[49]Takamasa OHNO, Makoto INOUE, Yukio OGIHARA, et al. Antimetastatic Activity of Acteoside, a Phenylethanoid Glycoside[J]. Biol. Pharm. Bull,2002,25(5):666
[50]Fumiko ABE, Tsuneatsu NAGAO, Hikaru OKABE. Antiproliferative Constituents in Plants 9. Aerial Parts of Lippia dulcis and Lippia canescens[J]. Biol. Pharm. Bull,2002,25(7):920
[51]邓敏,赵金垣,屠鹏飞,等.松果菊苷对TNFa诱导的SH-SY5Y细胞凋亡的保护作用[J].中国药理学通报,2005,21(2)：169
[52]Chi-Wai Lau,Zhen-Yu Chen,Chi-Ming Wong, et al. Attenuated endothelium-mediated relaxation by acteoside in rat aorta:Role of endothelial [Ca2+]i and nitric oxide/cyclic GMP pathway[J]. Life Sciences,2004,75:1149
[53]Marcello Pennacchio, Elizabeth Alexander, Yana M. Syah, et al. The efect of verbascoside on cyclic 3,5-adenosine monophosphate levels in isolated rat heart[J]. European Journal Pharmacology,1996,305:169
[54]Ki Yong LEE, Eun Ju JEONG, Heum-Sook LEE, et al. Acteoside of Callicarpa dichotoma Attenuates Scopolamine-Induced Memory Impairments[J]. Biol Pharm. Bull, 2006,29(1):71
[55]田枫,张阔,康爱君,等.松果菊苷改善SAM—P／8小鼠学习记忆能力作用机制初探[J].实验动物科学与管理,2006,23(2)：14
[56]赵欣,蒲小平,耿兴超.松果菊苷对帕金森病模型小鼠黑质纹状体蛋白表达影响的双向电泳分析[J].中国药理学通报,2008,24(1)：28
[57]Hisashi Matsuda, Toshio Morikawa, Hiromi Managi, et al. Antiallergic Principles from Alpinia galanga:Structural Requirements of Phenylpropanoids for Inhibition of Degranulation and Release of TNF-a and IL-4 in RBL-2H3 Cells[J]. Bioorganic & Medicinal Chemistry Letters.2003,13:3197
[58]Kyung Ah Koo, Seung Hyun Kim, Tae Hwan Oh, et al. Acteoside and its aglycones protect primary cultures of rat cortical cells from glutamate-induced excitotoxicity[J]. Life Sciences,2006,79:709
[59]Cunqin Jia, Haiming Shi, Xiangmei Wu, et al. Determination of echinacoside in rat serum by reversed-phase high-performance liquid chromatography with ultraviolet detection and its application to pharmacokinetics and bioavailability[J]. Journal of Chromatography B,2006,844:308
[60]A.Matthias, J.T. Blanchfield, K.G. Penman, I. Toch, C.S.Lang, J.J. De Voss, R.P. Lehmann, J. Clin. Pharm. Therapeut,2004,29:7
[61]A.Matthias, R.S. Addison, K.G Penman, R.G Dickinson, K.M. Bone, R.P. Lehmann. Life Sci,2005,77:2018
[62]A.Matthias, K.G. Penman, N.J. Matovic, K.M. Bone, J.J. De Voss, R.P. Lehmann, Molecules,2005,10:1242
[63]Cunqin Jia, Haiming Shi, Wei Jin, Ke Zhang, Yong Jiang, Mingbo Zhao, and Pengfei Tu. Metabolism of Echinacoside, a Good Antioxidant, in Rats:Isolation and Identification of Its Biliary Metabolites[J]. Drug Metabolism and disposition,2009, 37(2):431
[64]Yu-Tse Wu, Lie-Chwen Lin, Jung-Sung Sung, et al. Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely-moving rats using LC-MS/MS[J]. Journal of Chromatography B,2006,844:89
[65]雷厉,宋志宏,李寅增,等.管花肉苁蓉苯乙醇总苷在狗胃肠道内的生物转化[J].药学学报,2001,36(6)：432
[66]Yun-Xia Li, Xue-Hua Jiang, Hu-Yi Liang, et al. Determination of forsythiaside in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies[J]. Biomed. Chromatogr.2007,10:1002
[67]陈颖,远志活性成分的吸收和代谢研究。协和医科大学博士论文,2009
[1]X.L. Piao, E.J. Cho, M.H. Jang, J. Cui, Cytoprotective effect of lignans from Forsythia suspensa against peroxynitrite-induced LLC-PK1 cell damage[J]. Phytother. Res.,2009,23(7):938-942
[2]J. Han, M. Ye, H. Guo, M. Yang, B.R. Wang, D.A. Guo, Analysis of multiple constituents in a Chinese herbal preparation Shuang-Huang-Lian oral liquid by HPLC-DAD-ESI-MSn. J. Pharmaceut. Biomed. Anal.2007,44(2):430-438.
[3]Y.Y. Cui, S.Y. Feng, G. Zhao, M.Z. Wang, HPLC analysis of the active ingredients of Forsythia suspense[J]. Yao Xue Xue Bao.1992,27(8):603-608
[4]H.H. Qu, X.F. Zhai, B.X. Li, W.J. Sun, Study of the content of forsythiaside and forsythin from different parts of Forsythia suspensa(Thunb.)Vahl[J]. Yao Wu Fen Xi Za Zhi,2008,28(3):382-385
[5]D. Wang, Y.Y. Zhou, J. Harbin Univ. Commerce (Nat. Sci. Ed.) 2004,20:462
[6]W.H. Zhao, R.B. Shi, B. Liu, L.Z. Zhang, Determination of phillyrin and forsythoside A in Lianqiao Bingdu Qing capsule by RP-HPLC[J]. Zhongguo Zhong Yao Za Zhi,2005,30(1):36-39
[7]张炜,张汉明,郭美丽,杨继斌,朱美玲,HPLC法测定感冒退热颗粒(冲剂)中连翘酯苷A的含量。中草药,1999,30(4)：268-270
[8]H. Qu, Y. Zhang, Y. Wang, B. Li, W. Sun, Antioxidant and antibacterial activity of two compounds (forsythiaside and forsythin) isolated from Forsythia suspensa[J]. J. Pharm. Pharmacol.2008,60(2):261-266
[9]L.W. Zhang, C.G. Zhao, P. Yang, Study on the antioxidant activity and structure-activity relationship of forsythiaside [J]. Zhong Guo Yao Xue Za Zhi,2003, 38(5):334-336
[10]H.C. Ko, B.L. Wei, W.F. Chiou, Dual regulatory effect of plant extracts of Forsythia suspense on RANTES and MCP-1 secretion in influenza A virus-infected human bronchial epithelial cells[J]. J. Ethnopharmacol.2005,102(3):418-423
[11]胡克杰,徐凯建,王跃红,孙考祥,王栋,连翘酯甙体外抗病毒作用的实验研究[J]。 中国中医药科技,2001,8：89
[12]T. Iizuka, M. Nagai, Vasorelaxant effects of forsythiaside from the fruits of Forsythia suspense[J]. Yakugaku Zasshi,2005,125(2):219-224
[13]J. Liu, L.W. Zhang, Functions of Forsythiaside on the Damage of DNA Induced by Hydroxyl Radical[J]. Shanxi Zhong Yi Xue Yuan Xue Bao,2006,7(1):23-24
[14]B.N. Zhou, B.D. Bahler, G.A. Hofmann, M.R. Mattern, R.K. Johnson, D.G.I. Kingston, Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity[J]. J. Nat. Prod.,1998,61(11):1410-1412
[15]Y.X. Li, X.H. Jiang, H.Y. Liang, X. Li, Determination of forsythiaside in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies[J]. Biomed. Chromatogr.2008,22(4):361
[16]J.D. Wang, Q.Y. Chai, L.W. Zhang, Pharmacokinetics of Forsythiasie in Rats[J]. Shijie Kexue Jishu-Zhong Yi Yao Xian Dai Hua.2008,10(4):53-57
[17]R. Shi, Z. Xuan, Y. Ma, Y. Liu, H. Lu, T. Sun, Pharmacokinetics of forsythoside after intravenous administration in beagle dogs[J]. Eur. J. Drug Metab.Pharmacokinet. 2009,34(2):101-105
[18]Y.X. Li, C. Peng, R.Q. Zhang, X. Li, X.H. Jiang, Pharmacokinetics of phillyrin and forsythiaside following iv administration to Beagle dog [J].Eur. J. Drug Metab. Pharmacokinet.2009,34(2):79-83
[19]S.M. Dong, Q.Y. De. J. Asia Nat. Prod Res,1999,1:327
[20]L. W. Zhang, P. Study on the stability of forsythiasid[J]. Yang. Zhong Cheng Yao, 2003,25(5):353-356
[21]C.Q. Jia, H.M. Shi, W. Jin, K. Zhang, Y. Jiang, M.B. Zhao, P.F. Tu. Metabolism of echinacoside, a good antioxidant, in rats:isolation and identification of its biliary metabolites [J]. Drug Metab. Dispos.,2009,37(2):431-438
[22]Y.T. Wu, L.C. Lin, J.S. Sung, T.H. Tsai. Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely-moving rats using LC-MS/MS[J]. J. Chromatogr. B,2006,844:89-95
[23]Y. Chen, X.M. Liu, R.L. Pan, G.N. Wang, Y. Fu, Q. Chang. An LC-MS/MS method for determination of 3,6'-disinapoylsucrose in rat plasma and its application to a pharmacokinetic study[J]. Biomed. Chromatogr.,2009,23(12):1326-1332
[24]Okada T, Naraia, A, Matsunage S, Fusetani N, Shkimizu M. Assessment of the marine toxins by monitoring the integrity of human intestinal Caco-2 cell monolayers [J]. Toxicol In Vitro,2000,14(3):219-226
[25]Aiba T, Ishida K, Yoshinaga M, et al. Pharmacokinetic characterization of transcellular transport and drug interaction of digoxin in Caco-2 cell monolayers [J]. Biol Pharm Bull,2005,28(1):114-119
[26]Konsoula R, Bar Ilefa. Correlation of in vitro cytotoxicity with paracellular permeability in Caco-2 cells [J]. Toxicol In Vitro,2005,19(5):675-684
[27]Gresm C, Julian B, Bourrie M, et al. Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line:comparison with the parental Caco-2 cell line[J]. Pharm Res,1998,15(5):726-733
[28]Yee S Y. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997,14 (6):763-766
[29]Jung S J, Choi S O, Uma S Y. Prediction of the permeability of drugs through study on quantitative structure-permeability relationship[J]. J Pharm Biomed Anal,2006, 41(2):469-475
[30]Asano T, Ish Ihara K, Morota T, et al. Permeability of the flavonoids liquiritigenin and its glycosides in licorice roots and davidigenin, a hydrogenated metabolite of liquiritigenin, using human intestinal cell line Caco-2[J]. J Ethnopharmacol,2003, 89(2-3):285-289
[31]Annaert P, Gelder JV, Naesens L, et al. Carrier mechanisms involved in the transepithelial transport of bis(POM)-PMEA and its metabolites across Caco-2 monolayers[J].Pharm Res,1998,15(8):1168-1173
[32]Walgren RA, Karnaky KJ, Lindenmayer GE, et al. Pharmcol Expther,2000,294: 830
[33]Makhey VD, Guo A, Norris DA, et al. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells[J]. Pharm Res, 1998,15(8):1160-1167
[34]R.L. Cai, M. Wang, Y. Qi, X.Y. Wang, C. Xie, X.Z. Luo, Selection and Utilization on the Evaluation Criterions of Caco-2 Cell Model [J]. Zhong Guo Yao Xue Za Zhi.2008,43(24):1871-1874
[35]屠锡德,张钧寿,朱家璧主编.药剂学.第3版.北京：人民卫生出版社,2002.1219
[36]R. JE. Iowa State University Press,1999.63
[37]梁文权,生物药剂学与药物动力学.第2版.北京：人民卫生出版社,2000.122
© 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 |