Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance

Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance

The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a SNP in the drug metabolizing enzyme cytochrome, P450 3A43 (CYP3A43; rs472660) that highly significantly predicted o...

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Main Authors: Bigos, Kristin L., Bies, Robert R., Pollock, Bruce G., Lowy, Joshua J., Zhang, Fengyu, Weinberger, Daniel R.
Format: Online
Language:English
Published: 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100476/
id pubmed-3100476
recordtype oai_dc
spelling pubmed-31004762011-12-01 Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance Bigos, Kristin L. Bies, Robert R. Pollock, Bruce G. Lowy, Joshua J. Zhang, Fengyu Weinberger, Daniel R. Article The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a SNP in the drug metabolizing enzyme cytochrome, P450 3A43 (CYP3A43; rs472660) that highly significantly predicted olanzapine clearance in the CATIE trial (p=5.9e−7). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared to Caucasians (allele frequency 67% vs. 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable. 2011-04-26 2011-06 /pmc/articles/PMC3100476/ /pubmed/21519338 http://dx.doi.org/10.1038/mp.2011.38 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Bigos, Kristin L.
Bies, Robert R.
Pollock, Bruce G.
Lowy, Joshua J.
Zhang, Fengyu
Weinberger, Daniel R.
spellingShingle Bigos, Kristin L.
Bies, Robert R.
Pollock, Bruce G.
Lowy, Joshua J.
Zhang, Fengyu
Weinberger, Daniel R.
Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
author_facet Bigos, Kristin L.
Bies, Robert R.
Pollock, Bruce G.
Lowy, Joshua J.
Zhang, Fengyu
Weinberger, Daniel R.
author_sort Bigos, Kristin L.
title Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
title_short Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
title_full Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
title_fullStr Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
title_full_unstemmed Genetic Variation in CYP3A43 Explains Racial Difference in Olanzapine Clearance
title_sort genetic variation in cyp3a43 explains racial difference in olanzapine clearance
description The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a SNP in the drug metabolizing enzyme cytochrome, P450 3A43 (CYP3A43; rs472660) that highly significantly predicted olanzapine clearance in the CATIE trial (p=5.9e−7). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared to Caucasians (allele frequency 67% vs. 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100476/
_version_ 1611455386735345664

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