Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.

Steimer, W; Zopf, K; von Amelunxen, S; Pfeiffer, H; Bachofer, J; Popp, J; Messner, B; Kissling, W; Leucht, S

doi:10.1373/clinchem.2003.030825

2004

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Document type:: Journal Article; Multicenter Study; Article
Author(s):: Steimer, W; Zopf, K; von Amelunxen, S; Pfeiffer, H; Bachofer, J; Popp, J; Messner, B; Kissling, W; Leucht, S
Title:: Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.
Abstract:: BACKGROUND: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. METHODS: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). RESULTS: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). CONCLUSIONS: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.
Journal title abbreviation:: Clin Chem
Year:: 2004
Journal volume:: 50
Journal issue:: 9
Pages contribution:: 1623-33
Language:: eng
Fulltext / DOI:: doi:10.1373/clinchem.2003.030825
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/15205367
Print-ISSN:: 0009-9147
TUM Institution:: Institut für Klinische Chemie und Pathobiochemie; Klinik und Poliklinik für Psychiatrie und Psychotherapie
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Institut für Klinische Chemie und Pathobiochemie (Prof. Ruland)2004

mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Psychiatrie und Psychotherapie (Prof. Priller)2004