新型DPP-4抑制剂LGT-6在Caco-2细胞单层模型中的转运特性研究  

Transport Characteristics of Novel DPP-4 Inhibitor LGT-6 in Caco-2 Cell Monolayer Model

作　　者：张宇 班玉娟 王忠元[2] 张丽 汤磊 廖伟科 ZHANG Yu;BAN Yu-juan;WANG Zhong-yuan;ZHANG Li;TANG Lei;LIAO Wei-ke(School of Pharmacy,Guizhou Medical University,Guiyang 550004,China;Guizhou Provincial People's Hospital,Guiyang 550002;Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guiyang 550004,China)

机构地区：[1]贵州医科大学药学院,贵州贵阳550004 [2]贵州省人民医院,贵州贵阳550002 [3]贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550004

出　　处：《化学试剂》2021年第4期434-440,共7页Chemical Reagents

基　　金：贵州省科技支撑计划项目(黔科合支撑[2019]2761号);贵阳市科技计划项目(筑科合同[2017]5-7号);贵州省高层次创新型人才支持计划项目(黔科合人才(2016)4015号)。

摘　　要：通过建立Caco-2细胞单层模型探究降糖化合物LGT-6的转运特性。采用MTS法测定LGT-6的安全浓度范围,通过测定跨膜电阻、碱性磷酸酶活力、高渗透性药物普莱洛尔与低渗透性药物荧光素钠通透性实验的表观渗透系数P_(app)(AP→BL)来验证Caco-2细胞单层模型的致密性。考察LGT-6在从Transwell顶端(AP)到底端(BL)及底端到顶端的转运特性,计算表观渗透系数和外排比。分析转运时间、给药浓度和P-糖蛋白(P-gp)抑制剂对LGT-6转运特性的影响。Caco-2细胞单层模型建立成功,可用于LGT-6的转运特性研究。LGT-6的转运量随时间的延长及浓度的增大而增加,不同浓度的LGT-6在双向转运随浓度变化而变化,从AP→BL的P_(app)值为3.55×10^(-6)~5.64×10^(-6)cm/s,BL→AP的P_(app)为4.28×10^(-6)~8.76×10^(-6)cm/s,外排比(ER)均≥1.2。降糖化合物LGT-6在体外Caco-2细胞模型上的口服吸收较好,其转运方式主要以被动扩散为主,可能有P-糖蛋白参与其转运。To investigate the transport characteristics of hypoglycemic compound LGT-6,a Caco-2 cell monolayer model was established.MTS method was used to determine the safe concentration range of LGT-6.To verify the compactness of the Caco-2 cell monolayer model,transmembrane resistance,alkaline phosphatase activity and the apparent permeability coefficient P_(app)(AP→BL)of both high permeability drug Propranolol as well as low permeability drug fluorescein sodium was measured.Later investigation on the transport characteristics of LGT-6 from AP→BL and BL→AP obtained the apparent permeability coefficient(P_(app))and reflux ratio(ER).Furthermore,the impact of drug concentration,transport time and P-glycoprotein inhibitor on LGT-6 was also determined.The Caco-2 cell monolayer model was successfully established and can be used to investigate the transport characteristics of LGT-6.The transport volume of LGT-6 increases with the extension of time and concentration.The two-way transport of LGT-6 at different concentrations varies with the concentration.The P_(app)value from AP→BL is 3.55×10^(-6)to 5.64×10^(-6)cm/s as well as the P_(app)of BL→AP was 4.28×10^(-6)to 8.76×10^(-6)cm/s,the ER ratio was all greater than 1.2.The hypoglycemic compound LGT-6 exhibited a desirable oral absorption in an in vitro Caco-2 cell model,and the transport mode is mainly passive diffusion,P-glycoprotein may be involved in its transport.

关 键 词：CACO-2细胞单层模型 LGT-6 表观渗透系数 转运 P-糖蛋白 外排比 

分 类 号：R96[医药卫生—药理学]