title: The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients.
abstract: BACKGROUND
  Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, the CYP3A4*22 allele was reported to be associated with lower CYP3A4 expression and activity. Quetiapine, an antipsychotic metabolized by only CYP3A4, displayed higher serum levels in CYP3A4*22 carriers. Aripiprazole, haloperidol, pimozide, and risperidone are antipsychotics that are metabolized by CYP3A4 and CYP2D6. We investigated to which degree the CYP3A4*22 single-nucleotide polymorphism affects serum concentrations of patients receiving these drugs and compared this with the influence of CYP2D6 polymorphisms.
  
  
  METHODS
  Eight hundred thirty-four adult patients were included in this study, of whom 130 used aripiprazole, 312 used haloperidol, 86 used pimozide, and 396 used risperidone. Serum levels of the drug and, if available, their active metabolites were collected as well as information on dose. Patients were genotyped for CYP3A4*22 using restriction fragment length polymorphism analysis. Genotyping for CYP2D6 was done with allele-specific polymerase chain reaction.
  
  
  RESULTS
  No differences were found in serum (dose-corrected) concentrations of the antipsychotics between CYP3A4*22 wild-type and carrier groups. In contrast, CYP2D6 genotype did affect dose-corrected concentrations of the antipsychotics: for example, median dose-corrected concentrations were 56%, 86%, and 400% higher in predicted poor metabolizers versus extensive metabolizers for aripiprazole (P = 0.004), haloperidol (P > 0.001), and risperidone (P < 0.001), respectively, although a multiple regression analysis showed that only 4% to 17% of the variation in these concentrations could be explained by CYP2D6 status.
  
  
  CONCLUSIONS
  Heterozygous presence of CYP3A4*22 does not increase serum levels of antipsychotics metabolized by both CYP3A4 and CYP2D6, whereas CYP2D6 polymorphisms do affect serum levels to a limited extent.
authors: From the *Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk; and †GGz Centraal, Veldwijk, Ermelo, The Netherlands.
authors: Karen
authors: K
authors: van der Weide
authors: Jan
authors: J
authors: van der Weide
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000097:blood* / Q000493:pharmacokinetics; D000068180:Aripiprazole / Q000097:blood* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006220:Haloperidol / Q000097:blood* / Q000493:pharmacokinetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010868:Pimozide / Q000097:blood* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D018967:Risperidone / Q000097:blood* / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D010868:Pimozide; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006220:Haloperidol; D018967:Risperidone