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UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University. (Translational PKPD)ORCID iD: 0000-0002-1557-4416
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2012 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 92, no 2, 221-227 p.Article in journal (Refereed) Published
Abstract [en]

Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.

Place, publisher, year, edition, pages
2012. Vol. 92, no 2, 221-227 p.
Keyword [en]
blood-brain barrier, brain drug delivery, neuropharmacokinetics, neurotherapeutics, screening cascade, unbound-drug
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-222230DOI: 10.1038/clpt.2012.46PubMedID: 22713701OAI: oai:DiVA.org:uu-222230DiVA: diva2:711020
Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2014-04-09Bibliographically approved

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