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European Journal of Clinical Pharmacology

, Volume 66, Issue 5, pp 465–474 | Cite as

Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure—an impact similar to male gender or smoking in schizophrenic patients

  • Roza Ghotbi
  • Buster MannheimerEmail author
  • Eleni Aklillu
  • Akira Suda
  • Leif Bertilsson
  • Erik Eliasson
  • Urban Ösby
Pharmacogenetics

Abstract

Purpose

The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia.

Methods

A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine.

Results

In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact.

Conclusions

At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.

Keywords

Antipsychotics Drug metabolism Pharmacogenetics Polymorphism Therapeutic failure 

Notes

Acknowledgments

The study was supported by the Swedish Research Council, Medicine (grants 3902 and 10909), by the Stockholm County Council (ALF grants 20060420, 20060100, and 20080022), and by grants from the Department of Drug Management and Informatics, Stockholm County Council, and Söderström-Königska Hospital. We thank Professor Martin Schalling for his important contribution in planning and setting up the study of metabolic risks in psychosis. We also thank Lili Milani for excellent assistance in the development of the CYP1A2 Minisequencing technique and Carina Schmidt for her highly qualified administration of patient samples. Drs. Sören Akselson, Deanne Mannelid, and Helena Ring are acknowledged for recruiting most of the patients.

Supplementary material

228_2009_783_MOESM1_ESM.doc (35 kb)
Supplementary Table 1 Primer sequences for amplification of PCR fragments containing the polymorphisms, PCR fragment sizes, and restriction endonucleases used in PCR-RFLP (DOC 35 kb)
228_2009_783_MOESM2_ESM.doc (27 kb)
Supplementary Table 2 PCR primers and Minisequencing primers used for the genotyping of CYP1A2 729T>G and -163C>A (DOC 27 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Roza Ghotbi
    • 1
  • Buster Mannheimer
    • 1
    • 2
    • 3
    Email author
  • Eleni Aklillu
    • 1
  • Akira Suda
    • 1
    • 4
  • Leif Bertilsson
    • 1
  • Erik Eliasson
    • 1
  • Urban Ösby
    • 3
  1. 1.Department of Laboratory Medicine, Division of Clinical PharmacologyKarolinska University Hospital Huddinge–Karolinska InstitutetStockholmSweden
  2. 2.Department of Internal MedicineSödersjukhuset–Karolinska InstitutetStockholmSweden
  3. 3.Department of Clinical Neuroscience, R&D Unit, Department of PsychiatryDanderyd University Hospital–Karolinska InstitutetStockholmSweden
  4. 4.Department of PsychiatryYokohama City University School of MedicineYokohamaJapan

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