Genetic variation in CYP3A43 explains racial difference in olanzapine clearance

Kristin Bigos, R. R. Bies, B. G. Pollock, J. J. Lowy, F. Zhang, Daniel Weinberger

Research output: Contribution to journalArticle

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

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

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

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

Research output: Contribution to journalArticle

Bigos, Kristin ; Bies, R. R. ; Pollock, B. G. ; Lowy, J. J. ; Zhang, F. ; Weinberger, Daniel. / Genetic variation in CYP3A43 explains racial difference in olanzapine clearance. In: Molecular Psychiatry. 2011 ; Vol. 16, No. 6. pp. 620-625.
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