Genetic variation in CYP3A43 explains racial difference in olanzapine clearance

K. L. Bigos, Robert Bies, B. G. Pollock, J. J. Lowy, F. Zhang, D. R. Weinberger

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P5.9e-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 with 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.

Original languageEnglish
Pages (from-to)620-625
Number of pages6
JournalMolecular Psychiatry
Volume16
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

olanzapine
Antipsychotic Agents
Genotype
Clinical Medicine
Gene Frequency
Pharmaceutical Preparations
African Americans
Cytochrome P-450 Enzyme System
Single Nucleotide Polymorphism
Therapeutics
Alleles
Clinical Trials

Keywords

  • CYP3A43
  • CYP450
  • genetics
  • olanzapine
  • pharmacogenetics
  • pharmacokinetics

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Bigos, K. L., Bies, R., Pollock, B. G., Lowy, J. J., Zhang, F., & Weinberger, D. R. (2011). Genetic variation in CYP3A43 explains racial difference in olanzapine clearance. Molecular Psychiatry, 16(6), 620-625. https://doi.org/10.1038/mp.2011.38

Genetic variation in CYP3A43 explains racial difference in olanzapine clearance. / Bigos, K. L.; Bies, Robert; Pollock, B. G.; Lowy, J. J.; Zhang, F.; Weinberger, D. R.

In: Molecular Psychiatry, Vol. 16, No. 6, 06.2011, p. 620-625.

Research output: Contribution to journalArticle

Bigos, KL, Bies, R, Pollock, BG, Lowy, JJ, Zhang, F & Weinberger, DR 2011, 'Genetic variation in CYP3A43 explains racial difference in olanzapine clearance', Molecular Psychiatry, vol. 16, no. 6, pp. 620-625. https://doi.org/10.1038/mp.2011.38
Bigos, K. L. ; Bies, Robert ; Pollock, B. G. ; Lowy, J. J. ; Zhang, F. ; Weinberger, D. R. / Genetic variation in CYP3A43 explains racial difference in olanzapine clearance. In: Molecular Psychiatry. 2011 ; Vol. 16, No. 6. pp. 620-625.
@article{1006c11d21274ef484b9b475be124042,
title = "Genetic variation in CYP3A43 explains racial difference in olanzapine clearance",
abstract = "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 single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P5.9e-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 with 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.",
keywords = "CYP3A43, CYP450, genetics, olanzapine, pharmacogenetics, pharmacokinetics",
author = "Bigos, {K. L.} and Robert Bies and Pollock, {B. G.} and Lowy, {J. J.} and F. Zhang and Weinberger, {D. R.}",
year = "2011",
month = "6",
doi = "10.1038/mp.2011.38",
language = "English",
volume = "16",
pages = "620--625",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Genetic variation in CYP3A43 explains racial difference in olanzapine clearance

AU - Bigos, K. L.

AU - Bies, Robert

AU - Pollock, B. G.

AU - Lowy, J. J.

AU - Zhang, F.

AU - Weinberger, D. R.

PY - 2011/6

Y1 - 2011/6

N2 - 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 single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P5.9e-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 with 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.

AB - 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 single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P5.9e-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 with 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.

KW - CYP3A43

KW - CYP450

KW - genetics

KW - olanzapine

KW - pharmacogenetics

KW - pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=79957459409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957459409&partnerID=8YFLogxK

U2 - 10.1038/mp.2011.38

DO - 10.1038/mp.2011.38

M3 - Article

VL - 16

SP - 620

EP - 625

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 6

ER -