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The effect of MS-275 on CYP450 isoforms activity in rats by cocktail method
Qing Wu1, Qingwei Zhang2, Congcong Wen3
1The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
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.
Insights
MS-275, a histone deacetylase inhibitor, may induce cytochrome P450 enzyme activities in rats. This finding provides guidance for the safe co-administration of MS-275 with other medications.
Area of Science:
- Pharmacology
- Drug Metabolism
- Cancer Therapeutics
Background:
- MS-275 is a selective histone deacetylase inhibitor investigated for cancer treatment.
- Cytochrome P450 (CYP450) enzymes play a crucial role in drug metabolism.
- Understanding drug-drug interactions is vital for safe and effective cancer therapy.
Purpose of the Study:
- To evaluate the impact of MS-275 on the activity of major CYP450 isoforms in rats.
- To assess potential pharmacokinetic alterations when MS-275 is co-administered with other drugs.
Main Methods:
- A cocktail method was employed to assess multiple CYP450 isoforms (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4).
- Rats received varying doses of MS-275 via continuous intragastric administration for seven days.
- Probe drugs (bupropion, phenacetin, tolbutamide, metoprolol, midazolam, omeprazole) were administered, and plasma concentrations were analyzed using UPLC-MS/MS.
Main Results:
- MS-275 administration resulted in statistically significant pharmacokinetic differences for all probe drugs compared to the control group.
- Continuous administration of MS-275 for seven days appeared to induce the activities of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
- Potential induction of hepatocyte apoptosis was also observed.
Conclusions:
- MS-275 may induce the activity of major CYP450 enzymes in rats following prolonged administration.
- These findings suggest potential drug-drug interactions and necessitate careful consideration for co-administration with MS-275.
- Further research is warranted to elucidate the clinical implications for patients undergoing cancer therapy with MS-275.
