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CYP2C9 genotype vs. metabolic phenotype for individual drug dosing - a correlation analysis using flurbiprofen as probe drug

Please always quote using this URN: urn:nbn:de:bvb:20-opus-148783
  • Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinaryCurrently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type), and 0.113 for CYP2C9*3 (19 % of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19% would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation >= 20% and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40% off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.show moreshow less

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Metadaten
Author: Silvia Vogl, Roman W. Lutz, Gilbert Schönfelder, Werner K. Lutz
URN:urn:nbn:de:bvb:20-opus-148783
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Pharmakologie und Toxikologie
Language:English
Parent Title (English):PLoS ONE
Year of Completion:2015
Volume:10
Issue:3
Pagenumber:e0120403
Source:PLoS ONE 10(3): e0120403 (2015). DOI: 10.1371/journal.pone.0120403
DOI:https://doi.org/10.1371/journal.pone.0120403
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:4'-hydroxylation; allelic variant; cytochrome P450 2C9; impact pharmacogenetics; liver microsomes; tolbutamide substrate; warfarin polymorphisms
Release Date:2018/11/21
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International