Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS

Publication date: Available online 11 June 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Qingqing Yang, Jing Sun, Chuan Li, Haizhi Zhang, Weiren Xu, Changxiao Liu, Xuemin ZhengAbstractSpecific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α-hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC-MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC-MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by Km, Vmax and CLint. As a result, four CYP2D6 enzymes displayed diverse Km or Vmax towards MET and the values of CLint showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CLint*1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CLint*2/*1 = 74.87%) while CYP2D6*39 (CLint*39/*1 = 29.65%) and CYP2D6*10 (CLint*10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prom...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research