title: Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.
abstract: BACKGROUND
  We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females).
  
  
  METHODS
  All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses.
  
  
  RESULTS
  The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01).
  
  
  CONCLUSIONS
  The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact.
authors.affiliation: *Departments of Neuropsychiatry; and †Pharmacy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mihara
authors.forename: Akifumi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Shoko
authors.initials: S
authors.lastname: Kagawa
authors.forename: Goyo
authors.initials: G
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Nemoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068180:Aripiprazole; D044466:Asian People; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D015363:Quinolones / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; C517414:dehydroaripiprazole; D000068180:Aripiprazole; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A