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Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients.
Söderberg, M M; Haslemo, T; Molden, E; Dahl, M-L.
Afiliación
  • Söderberg MM; Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
Pharmacogenomics J ; 13(6): 544-50, 2013 Dec.
Article en En | MEDLINE | ID: mdl-23147717
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Óxidos / Oxigenasas / Benzodiazepinas / Trastornos Mentales Tipo de estudio: Diagnostic_studies Límite: Adolescent / Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Pharmacogenomics J Asunto de la revista: BIOLOGIA MOLECULAR / FARMACOLOGIA Año: 2013 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Óxidos / Oxigenasas / Benzodiazepinas / Trastornos Mentales Tipo de estudio: Diagnostic_studies Límite: Adolescent / Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Pharmacogenomics J Asunto de la revista: BIOLOGIA MOLECULAR / FARMACOLOGIA Año: 2013 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos