title: Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder: a population pharmacokinetic analysis.
abstract: Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach.
  
  
  
  This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine. CYP2D6*1, *2, *5, *10, and *41 polymorphisms were observed. A total of 306 steady-state concentrations for paroxetine were collected from the patients. A nonlinear mixed-effects model identified the apparent Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of paroxetine; the covariates included CYP2D6 genotypes, patient age, body weight, sex, and daily paroxetine dose.
  
  
  
  The allele frequencies of CYP2D6*1, *2, *5, *10, and *41 were 39.4, 14.5, 4.5, 41.1, and 0.6%, respectively. There was no poor metabolizer who had two nonfunctional CYP2D6*5 alleles. A one-compartment model showed that the apparent Km value was decreased by 20.6% in patients with the CYP2D6*10/*10 genotype in comparison with the other CYP2D6 genotypes. Female sex also influenced the apparent Km values. No PK parameters were affected by the presence of one CYP2D6*5 allele.
  
  
  
  Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.
authors.affiliation: aDivision of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences bCenter for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto cDepartment of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi dDepartment of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Mikito
authors.initials: M
authors.lastname: Ueda
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakashima
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogusu
authors.forename: Akiko
authors.initials: A
authors.lastname: Aoki
authors.forename: Shoko
authors.initials: S
authors.lastname: Tsuchimine
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsuda
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iwashita
authors.forename: Tatsumasa
authors.initials: T
authors.lastname: Ono
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oniki
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shimoda
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D019389:Cytochrome P-450 CYP2D6; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors