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1. Breast Care (Basel). 2012 Feb;7(1):25-31. Epub 2012 Feb 20.

The Discriminatory Value of CYP2D6 Genotyping in Predicting the
Dextromethorphan/Dextrorphan Phenotype in Women with Breast Cancer.

Trojan A, Vergopoulos A, Breitenstein U, Seifert B, Rageth C, Joechle W.

OnkoZentrum, Klinik im Park, Zürich, University Hospital of Zürich, Switzerland.

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.

PMCID: PMC3335358 [Available on 2013/2/1]
PMID: 22553469 [PubMed]