The effect of MS-275 on CYP450 isoforms activity in rats by cocktail method

Abstract

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.