丹红注射液对3种转运体的体外抑制作用研究  

Inhibition effects of Danhong injection on three transporters in human primary hepatocytes in vitro

作　　者：张婧娴[1] 陈涛 张湘奇[1] 石美智 陈君君 张科之 杨姣[1] 郭澄[1] 王来友 韩永龙[1] ZHANG Jingxian;CHEN Tao;ZHANG Xiangqi;SHI Meizhi;CHEN Junjun;ZHANG Kezhi;YANG Jiao;GUO Cheng;WANG Laiyou;HAN Yonglong(Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth PeoplesHospital, Shanghai 200233, China;College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, China;CarysBio Holdings CO.,LTD , Foshan 528000, Guangdong , China)

机构地区：[1]上海交通大学附属第六人民医院药剂科,上海200233 [2]广东药科大学药学院 [3]广东科志康新药开发有限公司

出　　处：《中国临床药理学与治疗学》2018年第4期389-394,共6页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金(81773949);上海市2014年度"科技创新行动计划"医学和农业领域项目(14401972002);上海市进一步加快中医药事业发展三年行动计划(2014年-2016年)(ZY3-RCPY-3-1036);上海市浦东新区科技发展基金民生科研(医疗卫生)项目(PKJ2017-Y07);上海市浦东新区卫生计生科技项目卫生行业科研专项(PW2017E-2)

摘　　要：目的:初步研究丹红注射液对药物转运体Na+-牛磺胆酸共转运多肽(NTCP)、有机阴离子转运多肽(OATP)和有机阳离子转运体1(OCT1)的体外抑制作用。方法:将新鲜的人原代肝细胞随机分为3组:实验组(7个不同含量的丹红注射液0.03%、0.06%、0.12%、0.25%、0.50%、1.00%和2.00%),NTCP、OATP和OCT1分别对应的阳性药物(环孢素A溶液10μmol/L、利福霉素200μmol/L、维拉帕米溶液20μmol/L)对照组和空白对照组(汉克斯平衡盐溶液),分别取160μL工作溶液置于人原代肝细胞体外孵育体系中预孵育15 min,再加入三合一底物40μL(牛胆磺酸钠5μmol/L、瑞舒伐他汀5μmol/L和1-甲基4-苯基吡啶离子5μmol/L)共同孵育。用液相色谱-串联质谱法测定细胞裂解液中代表转运体活性的底物含量,并计算其IC_(50)值。结果:在人原代肝细胞体外孵育体系中,0.12%,0.25%,0.50%,1.00%和2.00%的丹红注射液对OATP的抑制作用与空白对照组相比,差异均具有统计学意义(P<0.05,P<0.01,P<0.01,P<0.01,P<0.01)。丹红注射液对药物转运体NTCP、OATP和OCT1的IC_(50)值分别为≥2.00%、0.85%和>2.00%,且对OATP的IC_(50)值(0.85%)介于常用日剂量之间。结论:丹红注射液在体外对人原代肝细胞NTCP和OCT1有较弱的抑制作用,不太可能导致与它们相关的药物相互作用;但是对OATP有较强的抑制作用,提示我们当丹红注射液与其他经OATP转运的药物联用时,要注意药物间的相互作用,避免可能产生的不良反应。AIM：To study the inhibition effects of Danhong injection on NTCP, OATP and OCT1 in vitro. METHODS： The ceils were divided into three groups： experimental group （different content of Danhong injection 0.03%, 0.06%, 0.12%, 0.25%, 0.50%, 1.00% and 2.00%）, positive control group （cyclosporine A solution 10 μmol/L, rifamycin solution 200 μmol/L, verapamil solution 20 μmol/L） and blank control group （Hanks bal-ance salt solution）. One hundred and sixty microli-ters of working solution were incubated with human primary hepatocytes for 15 min and then mixed with 40 μL substrate （ox-gall sulfonic acid sodium 5 μmol/L, rosuvastatin 5 μmol/L and 1-methyl-4-phenyl pyridinium 5 μmol/L） , respectively. Con-tent of the substrate of cell lysis buffer was measured by liquid chromatography/tanderm mass spectrometry （LC-MS/MS） to determine the inhibition of Danhong injection towards transporters＂ activity and the inhibition effect were evaluated with 50% inhibi-tion concentration （ IC50） values. RESULTS： Com-pared with the blank control group, OATP was inhibited significantly by the 0.12%, 0.25%, 0.50%, 1.00% and 2.00% Danhong injection （P〈0.05, P〈0.01, P〈0.01, P〈0.01, P〈 0.01）. IC50 values of Danhong injection on NTCP, OATPand OCT1 were ≥2.00%, 0.85% and 〉 2.00%, respectively, and the value of 0.85% was between daily doses. CONCLUSION： Danhong injection has no show feeble inhibitory effect on NTCP and significant influence with OCT1, and may not lead to herbdrug interaction. But Danhong injection show strong inhibitory effect on OATP. Special attention should be paid to herbdrug interaction in drug combination to avoid possible adverse reaction.

关 键 词：丹红注射液 人原代肝细胞 转运体 抑制作用 药物相互作用 

分 类 号：R965.2[医药卫生—药理学]