目的 考察谷红注射液对体外及体内细胞色素P450（cytochrome P450，CYP450）酶的影响。方法 人肝微粒体“Cocktail”探针底物法进行体外酶抑制实验，检测7种探针底物代谢产物的相对生成量，计算半数抑制浓度（half inhibitory concentration，IC₅₀），评估谷红注射液（0.05%～10%）对7种CYP450亚酶抑制作用。人原代肝细胞体系进行体外酶诱导实验，分别检测酶活性及其mRNA表达水平，评估谷红注射液对CYP450酶诱导作用。采用整体动物法进行体内酶活性实验，检测7种特异性探针底物血浆药物浓度，评估谷红注射液（0.9、3.6 mL/kg）对大鼠7种CYP450亚酶活性的影响。结果 谷红注射液对人肝微粒体CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4的IC₅₀值分别为1.98%、7.95%、2.85%、5.39%、4.92%、7.76%和3.41%，均大于0.5%（理论临床最大血药浓度值）；人原代肝细胞CYP1A2、CYP2B6和CYP3A4 mRNA表达增加＞2倍，且前两者呈浓度相关性增加，对CYP1A2酶活性高于阳性对照40%。谷红注射液在超临床剂量下使大鼠CYP1A2、CYP2B6、CYP2C19和CYP3A4酶的体内探针底物茶碱、安非他酮、奥美拉唑和咪达唑仑的总清除率明显增加、系统暴露降低。结论 谷红注射液在临床剂量下对7种CYP450酶无显著抑制作用，但不排除高剂量下对CYP1A2、CYP2B6、CYP2C19和CYP3A4的诱导效应，建议开展使用敏感探针底物的临床试验以进一步确认潜在的药物相互作用。

Objective To investigate the effect of Guhong Injection (谷红注射液) on cytochrome P450 (CYP450) enzyme in vitro and in vivo. Methods The in vitro enzyme inhibition test was carried out by human liver microsomal “Cocktail” probe substrate method, the relative production of metabolites of seven kinds of probe substrates was detected, the half inhibition concentration (IC₅₀) was calculated, and the inhibitory effect of Guhong Injection (0.05%—10%) on seven kinds of CYP450 subenzymes was evaluated. In vitro enzyme induction test was carried out in human primary hepatocyte system to detect the enzyme activity and mRNA expression level, and evaluate the induction effect of Guhong Injection on CYP450 enzyme. The whole animal method was used to detect the plasma drug concentration of seven specific probe substrates and evaluate the effects of Guhong Injection (0.9,3.6mL/kg) on the activities of seven CYP450 subenzymes in rats. Results The IC₅₀ values of Guhong Injection on human liver microsome CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were 1.98%, 7.95%, 2.85%, 5.39%, 4.92%, 7.76% and 3.41%, respectively, all greater than 0.5% (theoretical clinical maximum blood drug concentration). The expressions of CYP1A2, CYP2B6 and CYP3A4 mRNA in human primary hepatocytes increased more than twice times, and the former two increased in a concentration-dependent manner; the activity of CYP1A2 enzyme was 40% higher than that of the positive control. The total clearance rates of theophylline, bupropion, omeprazole and midazolam, which were the probe substrates of CYP1A2, CYP2B6, CYP2C19 and CYP3A4 enzymes in rats, were significantly increased and systemic exposure decreased at ultra-clinical dose. Conclusion Guhong Injection has no significant inhibitory effect on seven CYP450 enzymes at clinical dose, but does not rule out the induction effect on CYP1A2, CYP2B6, CYP2C19 and CYP3A4 at high dose. It is suggested that clinical trials using sensitive probe substrates should be carried out to further confirm potential drug interactions.

R285.62

天津市教委科研计划项目（2021ZD030）