BACKGROUND: The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. METHODS: The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. RESULTS: From 151 patients predicted based on their genotype data for the 'traditional' CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. CONCLUSIONS: The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity.
BACKGROUND: The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. METHODS: The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. RESULTS: From 151 patients predicted based on their genotype data for the 'traditional' CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. CONCLUSIONS: The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity.
Authors: Matthew P Goetz; Stacey K Knox; Vera J Suman; James M Rae; Stephanie L Safgren; Matthew M Ames; Daniel W Visscher; Carol Reynolds; Fergus J Couch; Wilma L Lingle; Richard M Weinshilboum; Emily G Barr Fritcher; Andrea M Nibbe; Zeruesenay Desta; Anne Nguyen; David A Flockhart; Edith A Perez; James N Ingle Journal: Breast Cancer Res Treat Date: 2006-11-18 Impact factor: 4.872
Authors: Silvana Borges; Zeruesenay Desta; Lang Li; Todd C Skaar; Bryan A Ward; Anne Nguyen; Yan Jin; Anna Maria Storniolo; D Michele Nikoloff; Lin Wu; Grant Hillman; Daniel F Hayes; Vered Stearns; David A Flockhart Journal: Clin Pharmacol Ther Date: 2006-07 Impact factor: 6.875
Authors: Susan A Nowell; Jiyoung Ahn; James M Rae; Joshua O Scheys; Andrew Trovato; Carol Sweeney; Stewart L MacLeod; Fred F Kadlubar; Christine B Ambrosone Journal: Breast Cancer Res Treat Date: 2005-06 Impact factor: 4.872
Authors: M J Blake; A Gaedigk; R E Pearce; L R Bomgaars; M L Christensen; C Stowe; L P James; J T Wilson; G L Kearns; J S Leeder Journal: Clin Pharmacol Ther Date: 2007-02-14 Impact factor: 6.875
Authors: Vered Stearns; Michael D Johnson; James M Rae; Alan Morocho; Antonella Novielli; Pankaj Bhargava; Daniel F Hayes; Zeruesenay Desta; David A Flockhart Journal: J Natl Cancer Inst Date: 2003-12-03 Impact factor: 13.506
Authors: Monique J Bijl; Ron H N van Schaik; Laureen A Lammers; Albert Hofman; Arnold G Vulto; Teun van Gelder; Bruno H Ch Stricker; Loes E Visser Journal: Breast Cancer Res Treat Date: 2009-02-03 Impact factor: 4.872
Authors: William G Newman; Kristen D Hadfield; Ayshe Latif; Stephen A Roberts; Andrew Shenton; Christopher McHague; Fiona Lalloo; Sacha Howell; D Gareth Evans Journal: Clin Cancer Res Date: 2008-09-15 Impact factor: 12.531
Authors: Y Xu; Y Sun; L Yao; L Shi; Y Wu; T Ouyang; J Li; T Wang; Z Fan; T Fan; B Lin; L He; P Li; Y Xie Journal: Ann Oncol Date: 2008-04-11 Impact factor: 32.976
Authors: Andrea E Steuer; Corina Schmidhauser; Eva H Tingelhoff; Yasmin Schmid; Anna Rickli; Thomas Kraemer; Matthias E Liechti Journal: PLoS One Date: 2016-03-11 Impact factor: 3.240