Impact of <i>CYP1A2</i> and <i>CYP2D6</i> Polymorphisms on Drug Metabolism and on Insulin and Lipid Elevations and Insulin Resistance in Clozapine-Treated Patients
J Clin Psychiatry 2007;68(5):697-704
© Copyright 2015 Physicians Postgraduate Press, Inc.
Purchase This PDF for $40.00
If you are not a paid subscriber, you may purchase the PDF.
(You'll need the free Adobe Acrobat Reader.)
Receive immediate full-text access to JCP. You can subscribe to JCP online-only ($86) or print + online ($156 individual).
With your subscription, receive a free PDF collection of the NCDEU Festschrift articles. Hurry! This offer ends December 31, 2011.
If you are a paid subscriber to JCP and do not yet have a username and password, activate your subscription now.
As a paid subscriber who has activated your subscription, you have access to the HTML and PDF versions of this item.
Click here to login.
Did you forget your password?
Still can't log in? Contact the Circulation Department at 1-800-489-1001 x4 or send email
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.
Method: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).
Conclusion: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.