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Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
2013 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, Vol. 23, no 5, 279-285 p.Article in journal (Refereed) Published
Abstract [en]

Objective Metabolism of the atypical antipsychotic olanzapine (OLA) is partially catalyzed by cytochrome P450 (CYP) 1A2, a target of aryl hydrocarbon receptor (AHR)-mediated induction. We investigated the influence of four cis-acting polymorphisms (rs2470893C > T and rs2472297C > T between CYP1A1 and CYP1A2 loci, and rs762551C > A and rs2472304A > G within CYP1A2) as well as one trans-acting polymorphism upstream of the AHR locus (rs4410790C > T) on interindividual variation in systemic OLA exposure. Methods A cohort of 342 Caucasian psychiatric patients on long-term OLA treatment was genotyped using Illumina GoldenGate assays. The influence of haplotype and genotype was evaluated in terms of dose-adjusted steady-state serum concentrations (C/Ds) of OLA and the 4'-desmethyl OLA (DMO) to OLA ratio, a marker for CYP1A2-mediated metabolism of OLA. Results The CYP1A haplotype [rs2470893 (T)-rs2472297 (T)-rs762551 (A)] was associated with an increased DMO/OLA ratio and decreased C/Ds of OLA. This haplotype could not be tagged by rs762551 (A) but was tagged by rs2472297C > T, a single nucleotide polymorphism further identified as a significant covariate of the DMO/OLA ratio (P = 0.0001) and OLA C/D (P = 0.01). AHR rs4410790C > T influenced only the DMO/OLA ratio (P = 0.02). Among nonsmokers, patients carrying rs2472297 (T) and homozygous for rs4410790 (C) [n=26; mean=0.22, 95% confidence interval (CI) 0.19-0.26] showed a 1.7-fold higher mean DMO/OLA ratio compared with those carrying rs4410790 (T) and homozygous for rs2472297 (C) (n=50; mean=0.13, 95% CI 0.12-0.16, P = 0.0001), together with a nonsignificant decrease in the mean OLA C/D. Conclusion The reported influence of CYP1A2*1F (also known as CYP1A2-163A, rs762551C>A) on systemic OLA exposure could not be verified. CYP1A1/CYP1A2 rs2472297C > T and AHR rs4410790C > T are potentially useful genetic markers associated with variability in CYP1A2-mediated metabolism, but are of minor quantitative importance for systemic OLA exposure.

Place, publisher, year, edition, pages
2013. Vol. 23, no 5, 279-285 p.
Keyword [en]
4 '-desmethyl olanzapine, aryl hydrocarbon receptor, CYP1A2*1F, CYP1A2, drug metabolism, olanzapine, pharmacogenetics, single nucleotide polymorphisms, therapeutic drug monitoring
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-199700DOI: 10.1097/FPC.0b013e3283602876ISI: 000317399000004OAI: oai:DiVA.org:uu-199700DiVA: diva2:621292
Available from: 2013-05-14 Created: 2013-05-13 Last updated: 2013-05-14Bibliographically approved

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Söderberg, Mao M.
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