采用鸡尾酒法研究MS-275对大鼠细胞色素P450同工酶活性的影响。
The effect of MS-275 on CYP450 isoforms activity in rats by cocktail method.
作者信息
Wu Qing, Zhang Qingwei, Wen Congcong, Hu Lufeng, Wang Xianqin, Lin Guanyang
机构信息
The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
出版信息
Int J Clin Exp Pathol. 2015 Aug 1;8(8):9360-7. eCollection 2015.
MS-275, is a potent, class I selective histone deacetylase inhibitor currently in clinical trials for the cure of several types of cancer. The influence of MS-275 on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP2C19 were evaluated by cocktail method. The rats were randomly divided into MS-275 group (Low, Medium, High) and control group. The MS-275 group rats were given 12.3, 24.5, 49 mg/kg (Low, Medium, High) MS-275 by continuous intragastric administration for 7 days. The six probe drugs were given to rats through intragastric administration, and the plasma concentration were determinated by UPLC-MS/MS. The result of MS-275 group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide, metroprolol, midazolam and omeprazole. Continuous intragastric administration for 7 days may induce the activities of CYP2B6, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP2C19 of rats, and may induce the hepatocytes apoptosis. This may give advising for reasonable drug use after co-uesd with MS-275.
MS-275是一种强效的I类选择性组蛋白去乙酰化酶抑制剂，目前正处于治疗多种癌症的临床试验阶段。采用鸡尾酒法评估了MS-275对细胞色素P450同工酶CYP2B6、CYP1A2、CYP2C9、CYP2D6、CYP3A4和CYP2C19活性的影响。将大鼠随机分为MS-275组（低、中、高剂量）和对照组。MS-275组大鼠连续7天经胃内给药12.3、24.5、49mg/kg（低、中、高剂量）的MS-275。通过胃内给药将六种探针药物给予大鼠，并采用超高效液相色谱-串联质谱法测定血浆浓度。与对照组相比，MS-275组在安非他酮、非那西丁、甲苯磺丁脲、美托洛尔、咪达唑仑和奥美拉唑的药代动力学方面存在统计学差异。连续7天经胃内给药可能诱导大鼠CYP2B6、CYP1A2、CYP2C9、CYP2D6、CYP3A4和CYP2C19的活性，并可能诱导肝细胞凋亡。这可能为与MS-275联合使用后的合理用药提供参考。
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