title: Effect of CYP2D6 variants on venlafaxine metabolism in vitro.
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.
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Zhan
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Bing-Qing
authors.initials: BQ
authors.lastname: Liang
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Zhen-He
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Weng
authors.affiliation: b The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health , Beijing , China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: b The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health , Beijing , China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.affiliation: a School of Pharmacy, Wenzhou Medical University , Wenzhou , China and.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D000483:Alleles; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D002681:China; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000069468:Desvenlafaxine Succinate / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D006801:Humans; D007313:Insecta / Q000166:cytology; D008861:Microsomes / Q000201:enzymology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D013696:Temperature; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D000069470:Venlafaxine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D000069468:Desvenlafaxine Succinate
keywords: Allelic variants; CYP2D6 polymorphism; O-demethylation; drug metabolism; venlafaxine