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Clinical Pharmacogenetics of Olanzapine: with Focus on FMO Gene Polymorphisms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacogenetics is the study of variability in drug response attributed to genetic variation. Olanzapine (OLA) is a widely used antipsychotic drug for schizophrenia treatment. The pharmacokinetics of OLA display large inter-individual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need of individualized dosing in order to avoid concentration-dependent adverse effects and therapeutic failure. The observed variability has been partially explained by environmental and physiological factors. Genetically determined differences in drug metabolism represent a less studied source of variability. Precluded contribution by cytochrome P450 (CYP) 2D6 calls for evaluation of the other major OLA metabolizing enzymes. The objective of this thesis was to study pharmacogenetic influence of flavin-containing monooxygenase (FMO) 1 and 3, CYP1A2 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4 on therapeutic OLA exposure. We conducted genetic association studies applying gene re-sequencing and genotyping of candidate and tagging SNPs.

Patients carrying the FMO1*6 allele displayed increased dose-adjusted concentrations (C/Ds) of OLA, in serum as well as cerebrospinal fluid. Patients who were homozygous for the FMO3 K158-G308 compound variant showed reduced C/Ds of OLA N-oxide metabolite, but no alteration in OLA exposure. This compound variant is expected to have clinical relevance primarily for non-African populations, since low frequencies were detected among native Africans. Deviation in OLA exposure was observed in carrier of a rare FMO3 mutation, predicted in silico to affect gene splicing. Reduced OLA exposure was observed in UGT1A4*3 carriers. The CYP1A2 -163(A) (CYP1A2*1F) variant was not associated with increase in CYP1A2-catalyzed OLA metabolism or reduction in OLA exposure. Correlations were detected for two cis-acting variants within the inter-genetic region of the CYP1A cluster and a trans-acting variant located upstream the locus encoding aryl hydrocarbon receptor. The inconsistent data reported for CYP1A2*1F could be explained by presence of ethnic specific haplotype structures incorporating the -163(A) variant.

A continuously improved understanding of the wide range of factors that can influence pharmacokinetics and pharmacodynamics will increase the likelihood of achieving optimal treatment response for individual patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 805
Keyword [en]
olanzapine, pharmacogenetics, drug metabolism, schizophrenia, therapeutic drug monitoring, FMO1, FMO3, CYP1A2, UGT1A4
National Category
Pharmacology and Toxicology Psychiatry
Research subject
Clinical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-179957ISBN: 978-91-554-8454-5 (print)OAI: oai:DiVA.org:uu-179957DiVA: diva2:548339
Public defence
2012-10-15, Enghoffsalen, Akademiska sjukhuset, ingång 50, bv, Uppsala, 09:30 (Swedish)
Opponent
Supervisors
Available from: 2012-09-24 Created: 2012-08-27 Last updated: 2013-01-23Bibliographically approved
List of papers
1. Flavin-containing monooxygenase 3 polymorphisms in 13 ethnic populations from Europe, East Asia and sub-Saharan Africa: frequency and linkage analysis
Open this publication in new window or tab >>Flavin-containing monooxygenase 3 polymorphisms in 13 ethnic populations from Europe, East Asia and sub-Saharan Africa: frequency and linkage analysis
Show others...
2009 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 10, no 9, 1447-1455 p.Article in journal (Refereed) Published
Abstract [en]

AIMS: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E308G) and two African-specific (D132H and L360P) flavin-containing monooxygenase 3 (FMO3) polymorphisms. MATERIALS & METHODS: Allele frequencies were determined by TaqMan allelic discrimination assay in 2152 healthy volunteers from Europe (Swedes, Italians and Turks), East Asia (Japanese) and sub-Saharan Africa (nine ethnic groups covering eastern, southern and western regions), followed by haplotype and linkage analysis. RESULTS: Significant subpopulation differences (p < 0.001) in allele frequencies were found for E158K, V257M and E308G in Europeans and regional differences (p < 0.01) for D132H among Africans. No carrier of P360 was identified. Cis-linkage between G308 and K158 was confirmed with the compound variant (K158/G308) being found in a high proportion (12.0-38.3%) of non-African subjects, but rarely (1.3%) among Africans. CONCLUSIONS: Distribution of functionally relevant FMO3 polymorphisms varies not only between ethnicities but also within. The K158/G308 variant may have potential clinical importance primarily in non-African populations due to its low prevalence in Africa.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-124203 (URN)10.2217/pgs.09.77 (DOI)000270858700014 ()19761368 (PubMedID)
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
2. Interindividual Variation in Olanzapine Concentration Influenced by UGT1A4 L48V Polymorphism in Serum and Upstream FMO Polymorphisms in Cerebrospinal Fluid
Open this publication in new window or tab >>Interindividual Variation in Olanzapine Concentration Influenced by UGT1A4 L48V Polymorphism in Serum and Upstream FMO Polymorphisms in Cerebrospinal Fluid
2012 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 32, no 2, 287-289 p.Article in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-172302 (URN)10.1097/JCP.0b013e31824997a8 (DOI)000301121100023 ()
Available from: 2012-04-04 Created: 2012-04-04 Last updated: 2017-12-07Bibliographically approved
3. Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients
Open this publication in new window or tab >>Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients
2013 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 13, no 6, 544-550 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Pharmacology and Toxicology Psychiatry
Identifiers
urn:nbn:se:uu:diva-180427 (URN)10.1038/tpj.2012.47 (DOI)000327449700010 ()
Available from: 2012-09-06 Created: 2012-09-06 Last updated: 2017-12-07Bibliographically approved
4. Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure
Open this publication in new window or tab >>Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure
(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology Psychiatry
Identifiers
urn:nbn:se:uu:diva-180428 (URN)
Available from: 2012-09-06 Created: 2012-09-06 Last updated: 2013-01-23

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