银杏内酯A的BCS分类及吸收机制研究
投稿时间:2019-04-22     点此下载全文
引用本文:李楠楠,劳元圣,高尧春,李楠,张梦雪,黎迎,刘海波,董政起.银杏内酯A的BCS分类及吸收机制研究[J].中国现代中药,2020,22(3):370-378
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作者中文名作者英文名单位中文名单位英文名E-Mail
李楠楠 LI Nan-nan 哈尔滨商业大学 生命科学与环境科学研究中心,黑龙江哈尔滨150076 Center for Life Science and Environmental Sciences,Harbin University of Commerce,Harbin 150076,China  
劳元圣 LAO Yuan-sheng 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
高尧春 GAO Yao-chun 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
李楠 LI Nan 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
张梦雪 ZHANG Meng-xue 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
黎迎 LI Ying 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
刘海波 LIU Hai-bo 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China  
董政起 DONG Zheng-qi 中国医学科学院 药用植物研究所,北京100193 Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Beijing 100193,China 董政起,副研究员,研究方向:基于BCS分类的中药有效成分成药性评价研究;E-mail:dzq626@163.com 
基金项目:国家“重大新药创制”科技重大专项(2015ZX09501005);国家公益性行业科研专项(201507004);中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-012,2017-I2M-B&R-09)
中文摘要:目的:实验通过计算机模拟和体外快速实验研究银杏内酯A的生物药剂学分类(BCS)及其转运机制,分析其口服生物利用度不高的因素。方法:采用MOE、Discovery Studio、StarDrop软件对药物进行相关预测。采用2种不同的方法进行溶解度试验,以美国食品药品监督管理局(FDA)指导原则中的D0值和2015版《中华人民共和国药典》中的水中溶解度进行判断。渗透性采用体外细胞模型和人工渗透膜(PAMPA)模型,根据其表观渗透系数(Papp)和有效渗透率(Pe)的大小进行判断。结果:MOE预测结果显示银杏内酯A为难溶性药物;Discovery Studio预测结果表明银杏内酯A水溶性好,肠道吸收性质非常差;StarDrop预测银杏内酯A的溶解性为微溶,药物吸收率>30%,不受P-糖蛋白(P-gp)调控。选取pH 1.2、4.0、6.8磷酸缓冲液及水中银杏内酯A的D0值均大于1,可判断其为低渗透性药物。且其在水中的溶解度等于6×10-3 g·mL-1,为极微溶性药物。在Caco-2单层细胞模型中AP→BL转运实验中银杏内酯A的Papp为8.04×10-6~13.99×10-6 cm·s-1,在BL→AP转运实验中银杏内酯A的Papp为11.79×10-6~12.95×10-6 cm·s-1,因此可判断银杏内酯A为低渗透性药物。在PAMPA模型中,其Pe为0.089×10-6~0.098×10-6 cm·s-1,可以判断其为低渗透性药物。在高、中、低3个不同浓度的转运中,银杏内酯A的外排系数(ER)为1.11、0.62、0.89,均小于等于1.5。随着P-gp抑制剂维拉帕米的加入,银杏内酯A的转运速率无显著变化,且差异无统计学意义,说明其的转运不受P-gp的调控,以被动转运为主。结论:银杏内酯A为BCS Ⅳ类药物,溶解性和渗透性均较差,导致其口服生物利用度较低。
中文关键词:银杏内酯A  溶解性  渗透性  生物药剂学分类系统
 
Study on BCS Classification and Absorption Mechanism of Ginkgolide A
Abstract:Objective:To study the biopharmaceutical classification (BCS) and its transport mechanism of ginkgolide A by computer simulation and rapid in vitro experiments,and analyze the factors of low oral bioavailability.Methods:MOE,Discovery Studio,and StarDrop software were used to predict the drug.Solubility experiments were performed using two methods,judged by the D0 value in the US FDA guidelines and the solubility in water in the 2015 Chinese Pharmacopoeia.The permeability was determined using an in vitro cell model and a manual osmosis membrane (PAMPA)model based on the apparent permeability coefficient (Papp)and effective permeability (Pe).Results:The results of MOE prediction showed that ginkgolides A were poorly soluble drugs;the results of Discovery Studio showed that ginkgolides A had good water solubility and poor intestinal absorption properties;StarDrop predicted that the solubility of ginkgolides A was slightly soluble and drug absorption rate was more than 30%,not regulated by P-glycoprotein (P-gp).The D0 values of pH1.2,4.0,6.8 phosphate buffer and ginkgolides A in water were all greater than 1,and it was judged to be a low permeability drug.And its solubility in water is equal to 6×10-3 g·mL-1,which is a very slightly soluble drug.The apparent permeability coefficient Papp of ginkgolides A in the AP→BL transport experiment in the Caco-2 monolayer cell model was 8.04×10-6~13.99×10-6 cm·s-1,In the BL→AP transport experiment,the apparent permeability coefficient Papp of ginkgolides A was 11.79×10-6~12.95×10-6 cm·s-1,so it can be judged that ginkgolides A is a low-permeability drug.In the PAMPA model,the effective permeability Pe is 0.089×10-6 to 0.098×10-6 cm·s-1,which can be judged as a low-permeability drug.In the three different concentrations of high,medium and low transport,the ER values of ginkgolides A were 1.11,0.62,and 0.89,all of which were less than or equal to 1.5.With the addition of P-gp inhibitor verapamil,the transport rate of ginkgolide A did not change significantly,and there was no significant difference,indicating that its transport was not regulated by P-gp,and it was mainly passive transport.Conclusion:Ginkgolide A is a BCS class IV drug with poor solubility and permeability,resulting in low oral bioavailability.
keywords:ginkgolide A  solubility  permeability  biopharmaceutical classification
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