复方曲肽注射液对细胞色素P450酶活性的体内外影响 点击下载
| 论文标题： | 复方曲肽注射液对细胞色素P450酶活性的体内外影响 |
| 英文标题： | |
| 中文摘要： | 目的 考察复方曲肽注射液对细胞色素P450（CYP450）酶活性的体内外影响。方法将人肝微粒体与复方曲肽注射液（体积分数0.05%～10%）和CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4的特异性探针底物共孵育30min，采用超高效液相色谱-串联质谱（UPLC-MS/MS）技术检测相应代谢产物的生成量，并计算半数抑制浓度（IC50）；将人原代肝细胞与复方曲肽注射液（体积分数0.05%～10%）或CYP1A2、CYP2B6、CYP3A4阳性诱导剂共孵育48h后，采用实时荧光定量聚合酶链式反应法测定上述酶mRNA的相对表达量（即诱导倍数）。将雄性SD大鼠随机分为对照组（生理盐水+CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4探针底物8、2、1、1、10、10、8mg/kg）和实验组（复方曲肽注射液0.9mL/kg+CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4探针底物8、2、1、1、10、10、8mg/kg），每组6只，采用Cocktail探针药物法，以UPLC-MS/MS技术为手段，检测各探针底物的药动学参数。结果经0.05%～10%复方曲肽注射液处理后，人肝微粒体中CYP2B6、CYP2C8、CYP2C19的活性无明显变化，未能拟合出IC50；CYP1A2、CYP2C9、CYP2D6、CYP3A4的IC50分别为419.90%、97.78%、176.00%、19.42%；经0.05%～10%复方曲肽注射液处理后，人原代肝细胞（批号MHK）中CYP3A4mRNA的平均诱导倍数为4.88（且有2个浓度点的平均诱导倍数＞2）；经复方曲肽注射液干预后，CYP2C8、CYP2C9、CYP2C19底物的AUC0－t、AUC0－∞均显著升高，CYP2C8、CYP2C19底物的CL均显著降低，CYP2C9酶底物的t1/2显著延长（P＜0.05）。结论复方曲肽注射液对人肝微粒中CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP3A4活性无明显的体外抑制作用，对人原代肝细胞中CYP3A4mRNA的表达有体外诱导作用，对大鼠CYP2C8、CYP2C9、CYP2C19活性有体内抑制作用。 |
| 英文摘要： | OBJECTIVE To investigate the effects of Compound troxerutin and poreine cerebroside injection on the activity of cytochrome P450 （CYP450） enzyme in vivo and in vitro. METHODS Human liver microsomes were incubated with Compound troxerutin and poreine cerebroside injection （volume fraction 0.05%-10%） and the specific probe substrates of CYP1A2， CYP2B6， CYP2C8， CYP2C9， CYP2C19， CYP2D6 and CYP3A4 for 30 min. The production of corresponding metabolites was detected by ultra-high performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS）， and the half inhibitory concentration （IC50） was calculated. The relative mRNA expression （i.e. induction multiple） of CYP450 enzyme was determined by real-time fluorescence quantitative PCR after human primary hepatocytes were incubated with Compound troxerutin and poreine cerebroside injection （volume fraction 0.05%-10%） or 3 positive inducers of CYP1A2， CYP2B6， CYP3A4 for 48 hours. Male SD rats were randomly divided into control group （normal saline+probe substrates of CYP1A2， CYP2B6， CYP2C8， CYP2C9， CYP2C19， CYP2D6， CYP3A4 8， 2， 1， 1， 10， 10， 8 mg/kg） and experimental group （Compound troxerutin and poreine cerebroside injection 0.9 mL/kg+probe substrates of CYP1A2， CYP2B6， CYP2C8， CYP2C9， CYP2C19， CYP2D6， CYP3A4 8， 2， 1， 1， 10，10， 8 mg/kg）， with 6 rats in each group. The pharmacokinetic parameters of probe substrates were detected by UPLC-MS/MS and Cocktail probe drug method. RESULTS After the lzqpharm@126.com treatment of 0.05%-10% Compound troxerutin and poreine cerebroside injection， the activities of CYP2B6， CYP2C8 and CYP2C19 in human liver microsomes had no significant change， and IC50 could not be fitted； IC50 of CYP1A2， CYP2C9， CYP2D6 and CYP3A4 were 419.90%， 97.78%， 176.00%， 19.42%， respectively. After the treatment of 0.05%-10% Compound troxerutin and poreine cerebroside injection， the average induction multiple of CYP3A4 mRNA in human primary hepatocytes （No. MHK） was 4.88 （and the average induction multiples of 2 concentration points were higher than 2）. After the treatment of Compound troxerutin and poreine cerebroside injection， AUC0－t and AUC0－∞ of CYP2C8， CYP2C9 and CYP2C19 substrates were increased significantly， CL of CYP2C8 and CYP2C19 substrates were decreased significantly， while t1/2 of CYP2C9 substrate was prolonged significantly （P＜0.05）. CONCLUSIONS Compound troxerutin and poreine cerebroside injection has no obvious inhibitory effect on CYP1A2， CYP2B6， CYP2C8， CYP2C9， CYP2C19， CYP2D6 and CYP3A4 in human liver microsomes in vitro， but can induce the mRNA expression of CYP3A4 in human primary hepatocytes in vitro， and can inhibit the activities of CYP2C8， CYP2C9 and CYP2C19 in rats in vivo. |
| 期刊： | 2023年第34卷第16期 |
| 作者： | 刘凡琪；王婧媛；李楠；李自强；黄宇虹；王保和 |
| 英文作者： | LIU Fanqi，WANG Jingyuan，LI Nan，LI Ziqiang，HUANG Yuhong，WANG Baohe |
| 关键字： | 复方曲肽注射液；细胞色素P450；酶抑制；酶诱导；药物相互作用 |
| KEYWORDS： | Compound troxerutin and poreine cerebroside injection； cytochrome P450； enzyme inhibition； enzyme induction； |
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