Caco-2细胞单层模型构建及3种药物吸收机制评价
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摘要
目的:研究3种不同特性药物体外Caco-2细胞转运及其机制.方法:构建Caco-2细胞单层模型,选择酚酸类药物丹参总酚酸,生物碱类药物盐酸小檗碱和皂苷类药物三七皂苷R1为模型药物,研究3种不同特性药物经Caco-2细胞单层膜转运特点,分析其转运机制.结果:丹参总酚酸在酸性条件下经Caco-2细胞单层膜转运较高,无外排机制.盐酸小檗碱外排机制较强,不受pH的影响.三七皂苷R1经Caco-2细胞转运较差,但无外排机制,不受pH的影响.结论:3种药物口服吸收均较差,但机制不同.提高3种药物口服吸收的措施:提高丹参总酚酸在胃中滞留时间;消除盐酸小檗碱的外排影响;改善三七皂苷R1的膜透性.
Objective The transport mechanism of 3 kinds of drugs across Caco-2 cells in vitro were studied.Method Caco-2 cell monolayer model was constructed.Salvianolic acids(phenolic acid drugs),berberine hydrochloride(alkaloids drugs)and notoginsenoside R1(saponins drugs)were selected as model drugs.Transport characteristics of three kinds of drugs transport across Caco-2 cell monolayer were studied and their transport mechanism was analyzed.Result Salvianolic acids was highly transported across Caco-2 cell monolayer under acidic conditions without efflux effect.The efflux effect of berberine hydrochloride was strong,the transport was not affected by pH of the transport media.Notoginsenoside R1 was poorly transported across Caco-2 cells,but had no efflux effect and was not affected by pH of the transport media.Conclusion Oral absorption of the three drugs is not good,what's more,the mechanism is different.The strategies to improve the three drugs oral absorption are as follows:Improving the retention time of salvianolic acids in stomach;Reducing the efflux of berberine hydrochloride;Improving lipophilicity of notoginsenoside R1.
Objective The transport mechanism of 3 kinds of drugs across Caco-2 cells in vitro were studied.Method Caco-2 cell monolayer model was constructed.Salvianolic acids(phenolic acid drugs),berberine hydrochloride(alkaloids drugs)and notoginsenoside R1(saponins drugs)were selected as model drugs.Transport characteristics of three kinds of drugs transport across Caco-2 cell monolayer were studied and their transport mechanism was analyzed.Result Salvianolic acids was highly transported across Caco-2 cell monolayer under acidic conditions without efflux effect.The efflux effect of berberine hydrochloride was strong,the transport was not affected by pH of the transport media.Notoginsenoside R1 was poorly transported across Caco-2 cells,but had no efflux effect and was not affected by pH of the transport media.Conclusion Oral absorption of the three drugs is not good,what's more,the mechanism is different.The strategies to improve the three drugs oral absorption are as follows:Improving the retention time of salvianolic acids in stomach;Reducing the efflux of berberine hydrochloride;Improving lipophilicity of notoginsenoside R1.
引文
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[11]蒋学华,贾运涛,袁媛,等.Caco-2细胞模型在口服药物吸收过程研究中的应用[J].中国药学杂志,2002,37(5):7-9.
[12]Yamashita S,Konishi K,Yamazaki Y,et al.New and better protocols for a short-term Caco-2cell culture system[J].J Pharm Sci,2002,91(3):669-679.
[13]Ranaldi G,Consalvo R,Sambuy Y,et al.permeability characteristics of parental and clonal human intestinal Caco-2cell lines differentiated in serum-supplemented and serum-free media[J].Toicol In Vitro,2003,17(5-6):761-767.
[14]高东雁.丹参酚酸磷脂复合物及其自乳化给药系统研究[D].上海:复旦大学,2009.
[15]Zhang X,Qiu F,Jiang J,et al.Intestinal absorption mechanisms of berberine,palmatine,jateorhizine and coptisine:involvement of pglycoprotein[J].Xenobiotica,2011,41(4):290-296.
[2]Liu Z,Zheng X,Guo Y,et al.Quantitatively metabolic profiles of salvianolic acids in rats after gastric-administration of Salvia miltiorrhiza extract[J].Fitoterapia,2016,113:27-34.
[3]高东雁.丹参酚酸磷脂复合物及其自乳化给药系统研究[D].上海:复旦大学,2009.
[4]张英丰,李玉洁,杨庆,等.大鼠在体单向肠灌流法进行丹参素、丹酚酸B的肠吸收研究[J].中国实验方剂学杂志,2010,16(11):96-100.
[5]唐星.口服缓控释制剂[M].北京:人民卫生出版社,2007.
[6]谭晓梅,郭友立,钟玉飞.黄连提取物中盐酸小檗碱及药根碱大鼠在体肠吸收特征的研究[J].中国中药杂志,2010,35(6):755-758.
[7]张艳斌,崔元璐.环糊精包合作用对在体大鼠肠道P-糖蛋白药泵的影响[J].中国药理学通报,2008,24(10):1318-1323.
[8]肖学凤,乔晓莉,高岚,等.黄柏中盐酸小檗碱的药代动力学研究[J].天津中医药大学学报,2008,27(4):263-265.
[9]Gu B,Nakamichi N,Zhang WS,et al.Possible protection by notoginsenoside R1against glutamate neurotoxicity mediated by N-methylD-aspartate recep-tors composed of an NR1/NR2Bsubunit assembly[J].J Neurosci Res,2009,87(9):2145-2156.
[10]高坤,孙进,何仲贵.Caco-2细胞模型在口服药物吸收研究中的应用[J].沈阳药科大学学报,2005,22(6):73-78.
[11]蒋学华,贾运涛,袁媛,等.Caco-2细胞模型在口服药物吸收过程研究中的应用[J].中国药学杂志,2002,37(5):7-9.
[12]Yamashita S,Konishi K,Yamazaki Y,et al.New and better protocols for a short-term Caco-2cell culture system[J].J Pharm Sci,2002,91(3):669-679.
[13]Ranaldi G,Consalvo R,Sambuy Y,et al.permeability characteristics of parental and clonal human intestinal Caco-2cell lines differentiated in serum-supplemented and serum-free media[J].Toicol In Vitro,2003,17(5-6):761-767.
[14]高东雁.丹参酚酸磷脂复合物及其自乳化给药系统研究[D].上海:复旦大学,2009.
[15]Zhang X,Qiu F,Jiang J,et al.Intestinal absorption mechanisms of berberine,palmatine,jateorhizine and coptisine:involvement of pglycoprotein[J].Xenobiotica,2011,41(4):290-296.