title: Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients.
abstract: OBJECTIVE
  Adverse metabolic effects of atypical antipsychotics have increasingly been recognized. Recently, we found that levels of insulin and triglycerides increased by increasing serum clozapine concentration in clozapine-treated patients. As these insulin and triglyceride elevations probably are drug concentration-dependent, they also would be expected to be drug metabolism-related. The genetically polymorphic cytochromes P450 CYP1A2 and CYP2D6 catalyze the metabolism of clozapine. The aim of this study was to evaluate the impact of CYP1A2 and CYP2D6 polymorphisms on serum drug and metabolite levels and on insulin and triglyceride elevations and insulin resistance in patients receiving clozapine.
  
  
  METHODS
  Seventeen clozapine-treated patients were genotyped for CYP1A2 and CYP2D6 by polymerase chain reaction-based methods. Serum concentrations of clozapine and its N-desmethylmetabolite, blood glucose, and serum levels of insulin, C-peptide, triglycerides, and cholesterol were analyzed, and homeostasis model assessment index for insulin resistance (HOMA-IR) was determined.
  
  
  RESULTS
  Clozapine and N-desmethylclozapine concentration-to-dose (C/D) ratios were significantly higher in patients carrying 2 CYP1A2 single nucleotide polymorphisms (SNPs), previously suggested to cause low enzyme activity, compared to those with no such SNPs (p < .05). In contrast, clozapine and N-desmethylclozapine C/D ratios were not related to the CYP2D6 genotype. Furthermore, patients with elevated insulin levels more frequently carried CYP1A2*1C and/or *1D alleles, had higher clozapine and N-desmethylclozapine C/D ratios, and had higher lipid levels and HOMA-IR, compared to patients with normal insulin levels (p < .05).
  
  
  CONCLUSIONS
  CYP1A2 variants *1C and *1D seem to be associated with higher serum clozapine concentrations and an increased risk of developing insulin and lipid elevations and insulin resistance on a given dose of clozapine.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. Kristina.Melkersson@ki.se
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Melkersson
authors.forename: M Gabriella
authors.initials: MG
authors.lastname: Scordo
authors.forename: Arzu
authors.initials: A
authors.lastname: Gunes
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Dahl
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003024:Clozapine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D014150:Antipsychotic Agents; D007328:Insulin; D008055:Lipids; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D003024:Clozapine