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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

  • Pharmacogenetics
  • Published:
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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.

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References

  1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353(12):1209–1223

    Article  CAS  PubMed  Google Scholar 

  2. Bigos KL, Pollock BG, Coley KC, del Miller D, Marder SR, Aravagiri M et al (2008) Sex, race, and smoking impact olanzapine exposure. J Clin Pharmacol 48(2):157–165

    Article  CAS  PubMed  Google Scholar 

  3. Bachmann CJ, Haberhausen M, Heinzel-Gutenbrunner M, Remschmidt H, Theisen FM (2008) Large intraindividual variability of olanzapine serum concentrations in adolescent patients. Ther Drug Monit 30(1):108–112

    Article  CAS  PubMed  Google Scholar 

  4. Perry PJ, Lund BC, Sanger T, Beasley C (2001) Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine trial. J Clin Psychopharmacol 21(1):14–20

    Article  CAS  PubMed  Google Scholar 

  5. Gex-Fabry M, Balant-Gorgia AE, Balant LP (2003) Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 25(1):46–53

    Article  CAS  PubMed  Google Scholar 

  6. Kassahun K, Mattiuz E, Nyhart E Jr, Obermeyer B, Gillespie T, Murphy A et al (1997) Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 25(1):81–93

    CAS  PubMed  Google Scholar 

  7. Linnet K (2002) Glucuronidation of olanzapine by cDNA-expressed human UDP-glucuronosyltransferases and human liver microsomes. Hum Psychopharmacol 17(5):233–238

    Article  CAS  PubMed  Google Scholar 

  8. Ring BJ, Catlow J, Lindsay TJ, Gillespie T, Roskos LK, Cerimele BJ et al (1996) Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 276(2):658–666

    CAS  PubMed  Google Scholar 

  9. Bozina N, Kuzman MR, Medved V, Jovanovic N, Sertic J, Hotujac L (2008) Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients. J Psychiatr Res 42(2):89–97

    Article  PubMed  Google Scholar 

  10. Ehmer U, Vogel A, Schutte JK, Krone B, Manns MP, Strassburg CP (2004) Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Hepatology 39(4):970–977

    Article  CAS  PubMed  Google Scholar 

  11. Lindroos K, Sigurdsson S, Johansson K, Ronnblom L, Syvanen AC (2002) Multiplex SNP genotyping in pooled DNA samples by a four-colour microarray system. Nucleic Acids Res 30(14):e70

    Article  PubMed  Google Scholar 

  12. University of Geneva (2000) Arlequin: a software for population genetics data analysis. Ver 2.000 (computer program). Genetics and Biometry Lab, Department of Anthropology, University of Geneva

  13. Citrome L, Stauffer VL, Chen L, Kinon BJ, Kurtz DL, Jacobson JG et al (2009) Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol 29(3):278–283

    Article  CAS  PubMed  Google Scholar 

  14. Lund BC, Perry PJ (2000) Olanzapine: an atypical antipsychotic for schizophrenia. Expert Opin Pharmacother 1(2):305–323

    Article  CAS  PubMed  Google Scholar 

  15. Mauri MC, Steinhilber CP, Marino R, Invernizzi E, Fiorentini A, Cerveri G et al (2005) Clinical outcome and olanzapine plasma levels in acute schizophrenia. Eur Psychiatry 20(1):55–60

    Article  CAS  PubMed  Google Scholar 

  16. Nozawa M, Ohnuma T, Matsubara Y, Sakai Y, Hatano T, Hanzawa R et al (2008) The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). Ther Drug Monit 30(1):35–40

    Article  CAS  PubMed  Google Scholar 

  17. Mori A, Maruo Y, Iwai M, Sato H, Takeuchi Y (2005) UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos 33(5):672–675

    Article  CAS  PubMed  Google Scholar 

  18. Ghotbi R, Christensen M, Roh HK, Ingelman-Sundberg M, Aklillu E, Bertilsson L (2007) Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol 63(6):537–546

    Article  CAS  PubMed  Google Scholar 

  19. Sachse C, Brockmoller J, Bauer S, Roots I (1999) Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 47(4):445–449

    Article  CAS  PubMed  Google Scholar 

  20. Erichsen TJ, Ehmer U, Kalthoff S, Lankisch TO, Muller TM, Munzel PA et al (2008) Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene. Toxicol Appl Pharmacol 230(2):252–260

    Article  CAS  PubMed  Google Scholar 

  21. Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E (2008) Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol 64(4):381–385

    Article  CAS  PubMed  Google Scholar 

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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.

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Correspondence to Buster Mannheimer.

Additional information

Roza Ghotbi and Buster Mannheimer contributed equally and share first authorship.

Erik Eliasson and Urban Ösby contributed equally and share last authorship.

Akira Suda is a visiting scientist from the Department of Psychiatry, Yokohama City University School of Medicine, Japan

Erik Eliasson and Urban Ösby contributed equally and share last authorship.

Erik Eliasson and Urban Ösby contributed equally and share last authorship.

Akira Suda is a visiting scientist from the Department of Psychiatry, Yokohama City University School of Medicine, Japan

Electronic supplementary material

Below is the link to the electronic supplementary material.

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)

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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Ghotbi, R., Mannheimer, B., Aklillu, E. et al. 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. Eur J Clin Pharmacol 66, 465–474 (2010). https://doi.org/10.1007/s00228-009-0783-8

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  • DOI: https://doi.org/10.1007/s00228-009-0783-8

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