title: Effects of 24 CYP2D6 Variants Found in the Chinese Population on the Metabolism of Risperidone.
abstract: OBJECTIVE
  Cytochrome P450 (CYP450) 2D6 is an important member of the P450 enzyme superfamily and responsible for clearing 25% of clinically important drugs. The aim of this study was to assess the catalytic characteristics of 24 CYP2D6 allelic isoforms found in the Chinese population and their effects on the metabolism of risperidone in vitro.
  
  
  METHODS
  Insect microsomes expressing wild-type CYP2D6 and 24 CYP2D6 allelic variants were incubated with 20-1,000 μmol/l risperidone for 40 min at 37°C. After termination, risperidone and 9-OH risperidone, the metabolite of risperidone, were precipitated and used for signal collection by ultra-performance liquid-chromatography tandem mass spectrometry.
  
  
  RESULTS
  Among 24 CYP2D6 variants tested, 2 variants (CYP2D6*92 and CYP2D6*96) were found to be with no detectable activity. Two variants (E215K and R440C) exhibited higher intrinsic clearance values than the wild-type protein, while the remaining 20 CYP2D6 allelic variants exhibited significantly decreased clearance values (2.01-87.56%) compared to CYP2D6*1.
  
  
  CONCLUSIONS
  These findings suggest that more attention should be directed to subjects carrying these infrequent CYP2D6 alleles when administering risperidone in the clinic. This is the first report of all these novel alleles for risperidone metabolism, providing fundamental data for further clinical studies on CYP2D6 alleles.
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenling, PR China.
authors.forename: Zhen-He
authors.initials: ZH
authors.lastname: Wang
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Zhan
authors.forename: Yun-Xuan
authors.initials: YX
authors.lastname: Li
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D044466:Asian People / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007313:Insecta; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D011110:Polymorphism, Genetic; D018967:Risperidone / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone