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Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients

The Pharmacogenomics Journal volume 13, pages 544–550 (2013)Cite this article

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Abstract

The widely used antipsychotic drug, olanzapine (OLA) shows large interindividual variability in metabolic clearance. Although the role of the enzymes CYP1A2, CYP2D6 and UGT1A4 has been extensively explored, little is known about the in vivo role of flavin-containing monooxygenases (FMOs) catalyzing the N-oxidation of OLA in vitro. We investigated the influence of FMO1 and 3 polymorphisms on the steady state serum concentrations of OLA and its N-oxide metabolite in 379 patients. The upstream FMO1*6 was associated with increased dose-adjusted serum OLA concentrations (C/Ds; P=0.008), an effect further enhanced by FMO1rs7877C>T in smokers. The influence of FMO3 polymorphisms was limited to variability in OLA N-oxide. Homozygous carriers of FMO3rs2266780A>G (p.E308G) displayed 50% lower C/D of OLA N-oxide compared with subjects homo- or heterozygous for the A-variant (P<0.003). Our data support the role of FMO3 in the N-oxidation of OLA and implicate for the first time the contribution of FMO1 and its functional *6 variant in OLA disposition.

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Acknowledgements

We would like to thank Hilde Lunde at Center for Psychopharmacology Diakonhjemmet Hospital for assistance regarding re-analysis of OLA N-oxide concentrations in the TDM samples, Tomas Axelsson and the staff at The SNP&SEQ Technology Platform for their assistance with genotyping, and Maria Gabriella Scordo for helpful discussions on this manuscript.

Funding: The study was financially supported by the Swedish Research Council. The SNP&SEQ Technology Platform in Uppsala is supported by Uppsala University, Uppsala University hospital, the Swedish Council for Research Infrastructure and the Knut and Alice Wallenberg Foundation.

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Authors and Affiliations

  1. Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden

    M M Söderberg

  2. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway

    T Haslemo & E Molden

  3. Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

    M-L Dahl

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Correspondence to M M Söderberg.

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Söderberg, M., Haslemo, T., Molden, E. et al. Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients. Pharmacogenomics J 13, 544–550 (2013). https://doi.org/10.1038/tpj.2012.47

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