title: Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems.
abstract: OBJECTIVE
  This study evaluated the effects of cytochrome P450 (CYP) 2D6 polymorphisms on the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects and used paroxetine as a tool drug to compare the performance of traditional phenotype and activity score systems.
  
  
  METHODS
  Pharmacokinetic data were evaluated in 24 subjects who received a single oral dose of 25 mg controlled-release paroxetine. Plasma paroxetine concentrations were measured by LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Subjects were classified by two systems of phenotype prediction. In the traditional phenotype system, subjects were classified as extensive metabolizers or intermediate metabolizers; in the activity score system, subjects were divided into four activity groups. Analysis of variance testing was applied to estimate the effects of CYP2D6 polymorphisms on the pharmacokinetics of paroxetine.
  
  
  RESULTS
  With the traditional phenotype system, significant differences were observed in the following pharmacokinetic parameters of paroxetine: t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F (all P < 0.05). The AUC or exposure of paroxetine was about 3.5-fold higher in the intermediate metabolizer group than in the extensive metabolizer group. With the activity score system, significant differences were observed in the t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F among the four different activity score groups (all P < 0.05). We found that the AUC of paroxetine decreased by around one half as the activity score increased by 0.5.
  
  
  CONCLUSIONS
  The pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, 41 Damucang Alley, Xicheng District, Beijing, 100032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Haotian
authors.initials: H
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Kai
authors.initials: K
authors.lastname: Shen
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D002681:China; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D003692:Delayed-Action Preparations; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D017374:Paroxetine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D019389:Cytochrome P-450 CYP2D6; D003692:Delayed-Action Preparations; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors