Hide metadata

dc.date.accessioned2013-03-12T08:51:01Z
dc.date.available2013-03-12T08:51:01Z
dc.date.issued2010en_US
dc.date.submitted2010-03-24en_US
dc.identifier.citationRudberg, Ida. Impact of CYP2C19 genetics on pharmacokinetic variability of escitalopram and sertraline . Doktoravhandling, University of Oslo, 2010en_US
dc.identifier.urihttp://hdl.handle.net/10852/11881
dc.description.abstractEscitalopram and sertraline are among the most widely used drugs in the treatment of depression in Norway. Both drugs show substantial pharmacokinetic variability. Previous studies have indicated that the drug metabolising enzyme cytochrome P450 2C19 (CYP2C19), which exhibits extensive variability in activity due to genetic polymorphism, is involved in the metabolism of escitalopram and sertraline. The aim of this thesis was therefore to investigate the impact of CYP2C19 genetics on the pharmacokinetic variability of escitalopram and sertraline in psychiatric patients. By use of data from therapeutic drug monitoring, CYP2C19 genotype was shown to be a major determinant of the pharmacokinetics of escitalopram. On average, dose-adjusted serum concentration of escitalopram differed 9.7-fold between CYP2C19 poor metabolisers (PMs) and CYP2C19 ultrarapid metabolisers (UMs). Compared to CYP2C19 extensive metabolisers (EMs), the effect was more pronounced for CYP2C19 PMs than for UMs (5.7-fold higher vs. 42% lower mean dose-adjusted serum concentration, respectively). It was further identified that CYP2C19, besides catalysing the well known N-desmethylation of escitalopram, was able to catalyse formation of the propionic acid metabolite. The differences in serum concentration of escitalopram between CYP2C19 genotypes were most likely caused by a combined effect on the two metabolic pathways. Genetic variability in CYP2C19 was an important determinant of the pharmacokinetics of sertraline as well. Dose-adjusted serum concentration of sertraline was on average 3.2-fold higher in CYP2C19 PMs compared to EMs, but did not differ between CYP2C19 UMs and EMs. The substantial differences in pharmacokinetics of escitalopram and sertraline between CYP2C19 genotypes are of potential importance for the clinical response during treatment with these drugs. CYP2C19 UMs might constitute a subgroup of patients at increased risk of therapeutic failure, whereas CYP2C19 PMs are possibly at higher risk of dose-dependent side effects. Although further studies are needed to investigate the value of CYP2C19 genotyping in the prevention of therapeutic failure and side effects during treatment with escitalopram and sertraline, the findings of the present thesis may provide a fundament for individual dosing to limit variability in exposure of these drugs.eng
dc.language.isoengen_US
dc.relation.haspartPaper I Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Rudberg I, Hendset M, Uthus LH, Molden E, Refsum H. Therapeutic Drug Monitoring. 28:102-105, 2006. The paper is not available in DUO.
dc.relation.haspartPaper II Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E. Clininical Pharmacology and Therapeutics.83:322-327,2008. The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1038/sj.clpt.6100291
dc.relation.haspartPaper III Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Rudberg I, Hermann M, Refsum H, Molden E. European Journal of Clinical Pharmacology. 64:1181-1188, 2008. The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1007/s00228-008-0533-3
dc.relation.haspartPaper IV Identification of a novel CYP2C19-mediated metabolic pathway of S-citalopram in vitro. Rudberg I, Reubsaet JL, Hermann M, Refsum H, Molden E. Drug Metabolism and Disposition. 37:2340-2348, 2009. The paper is not available in DUO. The published version is available at: http://dx.doi.org/10.1124/dmd.109.029355
dc.relation.urihttp://dx.doi.org/10.1038/sj.clpt.6100291
dc.relation.urihttp://dx.doi.org/10.1007/s00228-008-0533-3
dc.relation.urihttp://dx.doi.org/10.1124/dmd.109.029355
dc.titleImpact of CYP2C19 genetics on pharmacokinetic variability of escitalopram and sertraline : a study based on therapeutic drug monitoring dataen_US
dc.typeDoctoral thesisen_US
dc.date.updated2010-06-30en_US
dc.creator.authorRudberg, Idaen_US
dc.subject.nsiVDP::568en_US
cristin.unitcode152300en_US
cristin.unitnameFarmasøytisk institutten_US
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft.au=Rudberg, Ida&rft.title=Impact of CYP2C19 genetics on pharmacokinetic variability of escitalopram and sertraline &rft.inst=University of Oslo&rft.date=2010&rft.degree=Doktoravhandlingen_US
dc.identifier.urnURN:NBN:no-24473en_US
dc.type.documentDoktoravhandlingen_US
dc.identifier.duo100194en_US
dc.contributor.supervisorEspen Molden, Helge Refsum, Monica Hermann & Hege Christensenen_US
dc.identifier.bibsys101140088en_US
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/11881/3/Rudberg-avhandling-publ.pdf


Files in this item

Appears in the following Collection

Hide metadata