两种天然药物对大鼠肠道药物吸收影响的研究
摘要
本文研究丁香酚和冰片对P-gp底物秋水仙碱和罗丹明123在大鼠小肠的吸收和外排影响,在此基础上研究新型给药系统纳米制剂和微乳制剂对药物吸收的影响,并进行体内药动学的研究。
采用扩散池试验技术,研究不同浓度的丁香酚、冰片对罗丹明123和秋水仙碱在吸收与外排方向上的影响,结果表明丁香酚和冰片在一定浓度范围内均可促进药物的肠道吸收,药物增渗倍数提高大约2-9倍。利用二元溶剂分散法制备的冰片纳米粒对罗丹明123吸收方向或外排方向的转运并没有产生明显的影响,可能与纳米粒的缓释作用有关。利用伪三元相图确定以Tween80为表面活性剂,无水乙醇为助表面活性剂,肉豆蔻异丙酯为油相,Km为3,丁香酚含量为2~4%的微乳配方,丁香酚微乳状态比非微乳状态明显促进了药物的吸收和抑制药物的外排,在吸收方向的增渗倍数为2.13,外排方向的抑制作用为0.34。在大鼠体内药动学研究中,吸收促进剂能显著增加秋水仙碱的吸收。秋水仙碱制备成含丁香酚的微乳后,2h内血药浓度较为平稳,且4h的血药浓度比其他组别高。
综上所述,丁香酚和冰片作为吸收促进剂,可提高药物胃肠吸收,增强药效,为临床药物的开发提供了依据。
The present study investigates the eugenol and borneol affect the absorption and secretion of colchicin and rhodamine123 by rat intestine cells through diffusion cell technology. On this basis, we probe into the novel drug deliver system nanoparitcle and microemuLsion affect the drug absorption and clarify the pharmacodynamic and pharmacokinetic parameters.
Research eugenol and bornelo contribute to the drug intestine absorption by the diffusion cell method. Eugenol and borneol contribute to the drug intestine absorption. The drug permeability (rhodamine 123 and colchicin) increase 2-9 times. We prepared borneol-PLGA nanoparticle through binary solvent dispersion method. We investigate the lower concentration of borneol adjust the permeability of rhodamine 123 through intestinal mucosa by the diffusion cell method. The results showed that nanoparticle form does not affect the absorption and secretion remarkably. We screened the formulation of microemuLsion through pseudo- ternary diagram and confirm the formuLation as following: Tween80 serve as surfactant, ethanol serve as aid-surfactant, isopropyl myristate serve as oil phase, Km is 3, eugenol content is 2~4%. MicroemuLsion formulation stimulates the absorption and inhibit the secretion remarkably compared with non-microemuLsion formuLation.
The absorption and secretion coefficient increase 2.13 and 0.34 times separately. The inhibition effects on secretion are more remarkable than stimuLation effects on absorption. The resuLts of pharmacodynamic and pharmacokinetic study in rat show: sorbefacient can stimulate absorption of colchicin remarkably and accelerate distribution and elimination in vivo. Colchicin microemuLsion formuLation containing eugenol acquired steady serum concentration in 2 hours and higher concentrations than other formuLations in 4 hours.
The results break a new path to create new formuLation P-gp antagonist, stimuLate drug absorption in intestine and improve the curative effect.
采用扩散池试验技术,研究不同浓度的丁香酚、冰片对罗丹明123和秋水仙碱在吸收与外排方向上的影响,结果表明丁香酚和冰片在一定浓度范围内均可促进药物的肠道吸收,药物增渗倍数提高大约2-9倍。利用二元溶剂分散法制备的冰片纳米粒对罗丹明123吸收方向或外排方向的转运并没有产生明显的影响,可能与纳米粒的缓释作用有关。利用伪三元相图确定以Tween80为表面活性剂,无水乙醇为助表面活性剂,肉豆蔻异丙酯为油相,Km为3,丁香酚含量为2~4%的微乳配方,丁香酚微乳状态比非微乳状态明显促进了药物的吸收和抑制药物的外排,在吸收方向的增渗倍数为2.13,外排方向的抑制作用为0.34。在大鼠体内药动学研究中,吸收促进剂能显著增加秋水仙碱的吸收。秋水仙碱制备成含丁香酚的微乳后,2h内血药浓度较为平稳,且4h的血药浓度比其他组别高。
综上所述,丁香酚和冰片作为吸收促进剂,可提高药物胃肠吸收,增强药效,为临床药物的开发提供了依据。
The present study investigates the eugenol and borneol affect the absorption and secretion of colchicin and rhodamine123 by rat intestine cells through diffusion cell technology. On this basis, we probe into the novel drug deliver system nanoparitcle and microemuLsion affect the drug absorption and clarify the pharmacodynamic and pharmacokinetic parameters.
Research eugenol and bornelo contribute to the drug intestine absorption by the diffusion cell method. Eugenol and borneol contribute to the drug intestine absorption. The drug permeability (rhodamine 123 and colchicin) increase 2-9 times. We prepared borneol-PLGA nanoparticle through binary solvent dispersion method. We investigate the lower concentration of borneol adjust the permeability of rhodamine 123 through intestinal mucosa by the diffusion cell method. The results showed that nanoparticle form does not affect the absorption and secretion remarkably. We screened the formulation of microemuLsion through pseudo- ternary diagram and confirm the formuLation as following: Tween80 serve as surfactant, ethanol serve as aid-surfactant, isopropyl myristate serve as oil phase, Km is 3, eugenol content is 2~4%. MicroemuLsion formulation stimulates the absorption and inhibit the secretion remarkably compared with non-microemuLsion formuLation.
The absorption and secretion coefficient increase 2.13 and 0.34 times separately. The inhibition effects on secretion are more remarkable than stimuLation effects on absorption. The resuLts of pharmacodynamic and pharmacokinetic study in rat show: sorbefacient can stimulate absorption of colchicin remarkably and accelerate distribution and elimination in vivo. Colchicin microemuLsion formuLation containing eugenol acquired steady serum concentration in 2 hours and higher concentrations than other formuLations in 4 hours.
The results break a new path to create new formuLation P-gp antagonist, stimuLate drug absorption in intestine and improve the curative effect.
引文
[1]李静,王广基.药物胃肠道吸收屏障及新型促吸收方法[J].药学学报Acta Pharmaceutica Sinica ,2005,40(7):600-605.
[2] Hunter J,Hirsr BH.Intestinal secretion of drugs.Therole of P-glycoprotein and related drug efflux system inlimiting oral drug absorption[J].Adv Drug Deliv Rev,1997,25(2-3):129-157.
[3]Yu DK.The contribution of P-glycoprotein to pharmacokineticdrug-drug interactions[J].J Clin Pharmo~ol,1999,39(12):1203-12l1.
[4]Meerum TJM,Malingre MM,Beijnen JH,et a1.Coadministration of oral cyclosporin A enables oraltherapy with paclitaxel[J].Clin Cancer Res,1 999,5(11):3379-3384.
[5]梁美蓉,刘启德,黄天来,等.冰片在大鼠血清和脑组织中的药代动力学特征[J].中药新药与临床药理,1993,4(4):38.
[6]赵保胜,刘启德.冰片促血脑屏障开放与病理性开放的比较[J].中药新药与临床药理,2002,13(5):287.
[7] Barry B W.Mode of action of penetration enhancers in human skin[J].Controlled Release,1987,6:85.
[8]樊岚岚,唐由之,卢景芬,等.冰片对兔角膜上皮细胞促渗透作用的实验研究[J],中国中医眼科杂志,1998,9(2):67-69.
[9]彭宅彪,张琼光,代虹健,丁英平.丁香酚的药理学研究进展[J].时珍国医国药,2006,17(10):2079-2081.
[10]俞永梅,张曦.HPLC法测定秋水仙碱片的含量[J].中国医药指南,2008,6(3):23-24.
[11] Qi Shen a,b, Yulian Lin a, Takahiro Handaa, et a1.Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies Inter national Journal of Pharmaceutics 313 (2006) 49–56.
[12]蒋新宇,周春山,唐课文.二元溶剂分散法制备PLA和PLGA纳米粒[J]应用化学,2003,20(8):732-735.
[13]黄利,侯世祥,毛声俊,梁栗等.均匀设计优化二元溶剂分散法制备莪术油纳米粒的研究.[J]中南药学,2006,4(6):416-418.
[14]寇欣.微乳给药系统的研究进展[J]2005,17(6):49-51.
[15]崔媛,杨学东,丁明玉.药用微乳处方设计概述.[J]中国医药工业杂志,2006,37(8):569-574.
[16]潘国梁,贾晓斌,魏惠华,王勇.药用微乳伪三元相图的几种制备方法比较研究.[J]中国药房,2006,17(1):21-23.
[17]张蕾,周庆华,吕鑫.微乳的制备及其在中药制剂中的应用.[J]中医药学报,2007,35(6)37-39.
[18]寇贺红.丁香酚纳米乳的研制[D].西北农林科技大学硕士论文,2006
[19]HaA,Keipert S.Development and characterization of microemulsions for ocular application[J].Eur JPharm Biopharm,1997,43(2):179-183.
[20]张柯萍,蔺胜照,陈国广,李学明.鸦胆子油微乳的制备及稳定性研究[J].华西药学杂志,2005,(20)3:l99-20l.
[21]张文娟.利福平微乳的研制[D].西北农林科技大学硕士论文,2006
[22]Qiu Hong CHEN, Shixiang HOU,Liang Chun GAN, Yuan Bo LI, Xiangrong SONG, Zheng CAI. Determination of Colchicine in Mouse Plasma by High Performance Liquid-chromatographic Method with UV Detection and Its Application to Pharmacokinetic Studies[J]. YAKUGAKU ZASSHI. 2007,127(9):1485-1490.
[23]李好枝.体内药物分析[M].北京,人民卫生出版社,2008:22-24.
[24] Rochdi M, Sabouraud A, Girre C, Venet R, Scherrmann JM. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects[J]. Eur J Clin Pharmacol, 1994, 46: 351–354.
[25]朱君荣,朱余兵,肖大伟,方伟蓉,李运曼.冰片对灯盏花素在大鼠体内药动学的影响[J].中国新药杂志,2007,16(22):1876-1878.
[26]中国药典2005版[M].二部附录XIX B,药物制剂人体生物利用度和生物等效性试验指导原则.附录173.
[27]陈艳明,王宁生.冰片对P糖蛋白的影响中药新药与临床药理2003,14(2):96-98.
[28]葛朝莉,韩漫夫,白润涛,于从,等.冰片促进血脑屏障开放的超微结构研究中西医结合心脑血管病杂志,2008,6(10):1183-1185
[29]Kaplan M. M., Alling D. W., Zimmerman H.J., WolfeH. J., Sepersky R. A., Hirsch G. S., N. Engl. [J]. J. Med., 1986, 315:1448-1454.
[30]Elisabeth Niel, Jean-Michel Scherrmann. Colchicine today[J]. Jiont Bone Spine, 2006, 73: 672-678.
[31]Baroli B,Lopez-Quintela MA,Delgado-Charro MB,etal.Microemulsions for topicaldelivery of 8-methoxsalen[J].J Control Release,2000,69(1):209-218.
[2] Hunter J,Hirsr BH.Intestinal secretion of drugs.Therole of P-glycoprotein and related drug efflux system inlimiting oral drug absorption[J].Adv Drug Deliv Rev,1997,25(2-3):129-157.
[3]Yu DK.The contribution of P-glycoprotein to pharmacokineticdrug-drug interactions[J].J Clin Pharmo~ol,1999,39(12):1203-12l1.
[4]Meerum TJM,Malingre MM,Beijnen JH,et a1.Coadministration of oral cyclosporin A enables oraltherapy with paclitaxel[J].Clin Cancer Res,1 999,5(11):3379-3384.
[5]梁美蓉,刘启德,黄天来,等.冰片在大鼠血清和脑组织中的药代动力学特征[J].中药新药与临床药理,1993,4(4):38.
[6]赵保胜,刘启德.冰片促血脑屏障开放与病理性开放的比较[J].中药新药与临床药理,2002,13(5):287.
[7] Barry B W.Mode of action of penetration enhancers in human skin[J].Controlled Release,1987,6:85.
[8]樊岚岚,唐由之,卢景芬,等.冰片对兔角膜上皮细胞促渗透作用的实验研究[J],中国中医眼科杂志,1998,9(2):67-69.
[9]彭宅彪,张琼光,代虹健,丁英平.丁香酚的药理学研究进展[J].时珍国医国药,2006,17(10):2079-2081.
[10]俞永梅,张曦.HPLC法测定秋水仙碱片的含量[J].中国医药指南,2008,6(3):23-24.
[11] Qi Shen a,b, Yulian Lin a, Takahiro Handaa, et a1.Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies Inter national Journal of Pharmaceutics 313 (2006) 49–56.
[12]蒋新宇,周春山,唐课文.二元溶剂分散法制备PLA和PLGA纳米粒[J]应用化学,2003,20(8):732-735.
[13]黄利,侯世祥,毛声俊,梁栗等.均匀设计优化二元溶剂分散法制备莪术油纳米粒的研究.[J]中南药学,2006,4(6):416-418.
[14]寇欣.微乳给药系统的研究进展[J]2005,17(6):49-51.
[15]崔媛,杨学东,丁明玉.药用微乳处方设计概述.[J]中国医药工业杂志,2006,37(8):569-574.
[16]潘国梁,贾晓斌,魏惠华,王勇.药用微乳伪三元相图的几种制备方法比较研究.[J]中国药房,2006,17(1):21-23.
[17]张蕾,周庆华,吕鑫.微乳的制备及其在中药制剂中的应用.[J]中医药学报,2007,35(6)37-39.
[18]寇贺红.丁香酚纳米乳的研制[D].西北农林科技大学硕士论文,2006
[19]HaA,Keipert S.Development and characterization of microemulsions for ocular application[J].Eur JPharm Biopharm,1997,43(2):179-183.
[20]张柯萍,蔺胜照,陈国广,李学明.鸦胆子油微乳的制备及稳定性研究[J].华西药学杂志,2005,(20)3:l99-20l.
[21]张文娟.利福平微乳的研制[D].西北农林科技大学硕士论文,2006
[22]Qiu Hong CHEN, Shixiang HOU,Liang Chun GAN, Yuan Bo LI, Xiangrong SONG, Zheng CAI. Determination of Colchicine in Mouse Plasma by High Performance Liquid-chromatographic Method with UV Detection and Its Application to Pharmacokinetic Studies[J]. YAKUGAKU ZASSHI. 2007,127(9):1485-1490.
[23]李好枝.体内药物分析[M].北京,人民卫生出版社,2008:22-24.
[24] Rochdi M, Sabouraud A, Girre C, Venet R, Scherrmann JM. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects[J]. Eur J Clin Pharmacol, 1994, 46: 351–354.
[25]朱君荣,朱余兵,肖大伟,方伟蓉,李运曼.冰片对灯盏花素在大鼠体内药动学的影响[J].中国新药杂志,2007,16(22):1876-1878.
[26]中国药典2005版[M].二部附录XIX B,药物制剂人体生物利用度和生物等效性试验指导原则.附录173.
[27]陈艳明,王宁生.冰片对P糖蛋白的影响中药新药与临床药理2003,14(2):96-98.
[28]葛朝莉,韩漫夫,白润涛,于从,等.冰片促进血脑屏障开放的超微结构研究中西医结合心脑血管病杂志,2008,6(10):1183-1185
[29]Kaplan M. M., Alling D. W., Zimmerman H.J., WolfeH. J., Sepersky R. A., Hirsch G. S., N. Engl. [J]. J. Med., 1986, 315:1448-1454.
[30]Elisabeth Niel, Jean-Michel Scherrmann. Colchicine today[J]. Jiont Bone Spine, 2006, 73: 672-678.
[31]Baroli B,Lopez-Quintela MA,Delgado-Charro MB,etal.Microemulsions for topicaldelivery of 8-methoxsalen[J].J Control Release,2000,69(1):209-218.