丹红注射液对人原代肝细胞尿苷二磷酸葡萄糖醛酸转移酶的体外抑制作用  

Inhibition effects of Danhong injection on UDP-glucuronyl transferase in human primary hepatocytes in vitro

作　　者：张婧娴[1] 张湘奇[1] 石美智 张素行 张科之 杨姣[1] 郭澄[1] 韩永龙[1] 

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]广东中西达一新药开发有限公司,佛山200233

出　　处：《中国临床药理学杂志》2017年第1期44-46,50,共4页The Chinese Journal of Clinical Pharmacology

基　　金：上海市"科技创新行动计划"医学和农业领域2014年基金资助项目(14401972002);上海市进一步加快中医药事业发展三年行动计划(2014-2016年)基金资助项目(ZY3-RCPY-3-1036)

摘　　要：目的研究丹红注射液对Ⅱ相药物代谢酶尿苷二磷酸葡萄糖醛酸转移酶(UGTs)的体外抑制作用。方法随机将新鲜的人原代肝细胞分为3组:实验组(丹红注射液)、阳性对照组(酮康唑)和空白对照组。分别将7个不同含量的丹红注射液(0.14%,0.41%,1.23%,3.70%,11.10%,33.30%和100.00%)、不同浓度的酮康唑溶液(1.37,4.12,12.30,37.00,111.00,333.00和1000.00μmol·L^(-1))10μL和纯化水与探针底物7-羟基香豆素(1000μmol·L^(-1))10μL置于人原代肝细胞体外孵育体系80μL中,共同孵育15 min。用液相色谱-串联质谱法测定代谢产物7-羟基香豆素-D-葡萄糖醛酸苷的含量(代表UGTs活性),并计算其IC50值(表示丹红注射液对UGTs的抑制程度)。结果含量分别为0.00%,0.01%,0.04%,0.12%,0.37%,1.11%,3.33%和10.00%的丹红注射液(在孵育体系中稀释了10倍)对UGTs的抑制率分别为0,-1.6%,3.2%,8.2%,5.2%,17.1%,38.3%和71.4%,且呈浓度依赖性抑制作用。与空白对照组比较,1.11%,3.33%,10.00%的丹红注射液差异均有统计学意义(P<0.05)。在人原代肝细胞体外孵育体系中,丹红注射液对UGTs的IC50值为4.9%。结论丹红注射液对人原代肝细胞UGTs有较弱的抑制作用,不太可能导致与UGTs相关的药物相互作用。Objective To study the inhibition effects of Danhong injection on UDP-glucuronyl transferase（UGTs） isoforms in vitro. Methods The experiment was divided into three groups： experimental group（ Danhong injection）,positive control group（ ketoconazole） and blank control group. Ten microliters of different content of Danhong injection（ 0. 14%,0. 41%,1. 23%,3. 70%,11. 10%,33. 30% and 100. 00%）,different concentration of ketoconazole solution（1. 37,4. 12,12. 30,37. 00,111. 00,333. 00 and 1000. 00 μmol·L-1） and purified water were incubated with human primary hepatocytes in the presence of 10 μL7- hydroxycoumarin（7-HC）（ 1000. 00 μmol·L-1） for 15 min respectively. In vitro glucuronidation of 7-hydroxycoumarin（7-HC-glucuronide） reaction was employed as the probe reaction to determine the inhibition of Danhong injection towards UGTs＇ activity and the inhibitory effect were evaluated with 50% inhibitory concentration（IC_（50）） values.UGTs probe substrate metabolite（ 7- HC- glucuronide） was measured by liquid chromatography / tanderm mass spectrometry（ LC- MS / MS）. Results The inhibition ratios of different contents（ 0. 00 %,0. 01 %,0. 04 %,0. 12 %,0. 37 %,1. 11 %,3. 33 % and 10. 00 %） Danhong injection（diluted 10 times in incubation system） on UGTs were 0,- 1. 6 %,3. 2 %,8. 2 %,5. 2 %,17. 1 %,38. 3 % and 71. 4 % respectively with concentration dependent inhibition. Compared with the blank control group,UGTs were inhibited significantly by the 1. 11 %,3. 33 % and 10. 00 % Danhong injection（P〈0. 05）. IC_（50） value of Danhong injection on UGTs was 4.9%.Conclusion Danhong injection show feeble inhibitory effect on UGTs isoforms,and may not lead to herb-drug interactions.

关 键 词：丹红注射液 人原代肝细胞 尿苷二磷酸葡萄糖醛酸转移酶 抑制作用 药物相互作用 

分 类 号：R28[医药卫生—中药学]