title: Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro.
abstract: OBJECTIVE
  The aim of this article was to assess the catalytic activities of 24 cytochrome P450 2D6 (CYP2D6) variants found in the Chinese population toward atomoxetine in vitro as well as CYP2D6.1.
  
  
  METHODS
  In this study, the co-expression enzyme of human recombinant CYPOR, CYPb5, and CYP2D6.1 or other CYP2D6 variants with the baculovirus-mediated insect cells (Sf21) was used to study the catalytic activities of 24 CYP2D6 variants toward atomoxetine metabolism. The metabolite of atomoxetine (4-hydroxyatomoxetine) was detected by ultra-high performance liquid chromatography-mass spectrometry method.
  
  
  RESULTS
  The intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with CYP2D6.1. CYP2D6.94, CYP2D6.D336N, CYP2D6.R440C exhibited marked increased values 172, 126, 121% respectively. CYP2D6.89 and CYP2D6.98 exhibited similar catalytic activity as the wild type, whereas 17 variants exhibited significantly decreased values (from 5 to 87%) due to increase Km and/or decrease Vmax values. However, CYP2D6.92 and CYP2D6.96 showed no or few activity because of producing nothing.
  
  
  CONCLUSIONS
  Our results suggest that most of these newly found variants exhibit significantly changed catalytic activities compared with the wild type. And these findings provide valuable information for the growth and development of personalized medicine in China.
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenzhou, China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Liang
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhan
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Ermin
authors.initials: E
authors.lastname: Gu
authors.forename: Dapeng
authors.initials: D
authors.lastname: Dai
authors.forename: Jianping
authors.initials: J
authors.lastname: Cai
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D044466:Asian People; D000069445:Atomoxetine Hydrochloride / Q000493:pharmacokinetics*; D002681:China; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D010636:Phenols / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism; D061987:Sf9 Cells
chemical_list: D010636:Phenols; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; C454679:4-hydroxyatomoxetine; D019389:Cytochrome P-450 CYP2D6