Effect of CYP2D6 variants on venlafaxine metabolism in vitro |
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| Authors: | Yun-Yun Zhan Bing-Qing Liang Hao Wang Zhen-He Wang Qing-Hua Weng Da-Peng Dai |
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| Institution: | 1. School of Pharmacy, Wenzhou Medical University, Wenzhou, China and;2. The Key Laboratory of Geriatrics, Beijing Hospital &3. Beijing Institute of Geriatrics, Ministry of Health, Beijing, China |
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| Abstract: | 1.?CYP2D6 is an important member of the cytochrome P450 (CYP450) enzyme superfamily, we recently identified 22 CYP2D6 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of venlafaxine in vitro.2.?The wild-type and 24 CYP2D6 variants were expressed in insect cells, and each variant was characterized using venlafaxine as the substrate. Reactions were performed at 37?°C with 5–500?μM substrate (three variants was adjusted to 1000?μM) for 50?min. By using high-performance liquid chromatography to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of O-desmethylvenlafaxine were determined.3.?Among the 22 CYP2D6 variants, the intrinsic clearance (Vmax/Km) values of all variants were significantly decreased (from 0.2% to 84.5%) compared with wild-type CYP2D6*1. In addition, the kinetic parameters of two CYP2D6 variants could not be detected because they have no detectable enzyme activity.4.?The comprehensive in vitro assessment of CYP2D6 variants provides significant insights into allele-specific activity towards venlafaxine in vivo. |
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| Keywords: | Allelic variants CYP2D6 polymorphism drug metabolism O-demethylation venlafaxine |
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