title: Effects of 22 novel CYP2D6 variants found in Chinese population on the metabolism of dapoxetine.
abstract: BACKGROUND
  CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure.
  
  
  RESULTS
  The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96,*97, *98, *R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with the counterpart of CYP2D6*1, with most of these variants exhibiting either reduced Vmax and/or increased Km values. For dapoxetine demethylation pathway (which produces desmethyldapoxetine), 2D6*89 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide), the relative clearance values of three variants, 2D6*90, *94, and V342M, exhibited no markedly increased relative clearance of 106.17%, 107.78%, and 109.98%, respectively; the rest 19 variants exhibited significantly decreased levels ranging from 27.56% to 84.64%. In addition, the kinetic parameters of two CYP2D6 variants (2D6*92 and 2D6*96) could not be detected, due to the defect of the CYP2D6 gene.
  
  
  CONCLUSIONS
  As the first report of all aforementioned alleles for dapoxetine metabolism, these data may help in the clinical assessment of the metabolic elimination of dapoxetine and may provide fundamental information for further clinical studies.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Ren-ai
authors.initials: RA
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Er-min
authors.initials: EM
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, People's Republic of China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001596:Benzylamines / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes / Q000378:metabolism*; D011110:Polymorphism, Genetic
chemical_list: D001596:Benzylamines; D009281:Naphthalenes; D019389:Cytochrome P-450 CYP2D6; C080598:dapoxetine
keywords: CYP2D6 variants; dapoxetine; drug metabolism; genetic polymorphism; personalized treatment