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Influence of CYP2D6 and CYP3A4 Phenotypes, Drug Interactions, and Vitamin D Status on Tamoxifen Biotransformation.

Therapeutic drug monitoring (2015-04-09)
Marina V Antunes, Tatiana Aparecida da Fontoura Timm, Vanessa de Oliveira, Dilana E Staudt, Suziane Raymundo, Gustavo Gössling, Jorge V Biazús, José A Cavalheiro, Daniela D Rosa, Pierre Wallemacq, Vincent Haufroid, Rafael Linden, Gilberto Schwartsmann
ABSTRACT

In view of the large variability on therapeutic response and the multiple factors associated to tamoxifen (TAM) metabolic activation, this study aimed to evaluate the effect of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D exposure on TAM metabolism in a group of breast cancer patients. Trough blood samples were collected from 116 patients. TAM and metabolites endoxifen (EDF), N-desmethyltamoxifen, and 4-hydroxytamoxifen (HTF) were measured in plasma by liquid chromatography-tandem mass spectrometry. CYP2D6 and CYP3A4 phenotyping were obtained according to [dextromethorphan]/[dextrorphan] and [omeprazole]/[omeprazole sulfone] metabolic ratios, measured by high-performance liquid chromatography in plasma collected 3 hours after oral administration of 33 mg of dextromethorphan and 20 mg of omeprazole. Vitamin D3 was measured in plasma by high-performance liquid chromatography-ultraviolet. Data on concomitant use of drug considered as CYP2D6 and CYP3A4 inhibitor or inducer and vitamin D supplementation were recorded. About 20% of patients had reduced CYP2D6 metabolic activity and 7% CYP3A4 impaired metabolism. EDF levels diminished proportionally to the reduction of CYP2D6 metabolic activity (poor metabolizer 2.79 ng·mL, intermediate metabolizer (IM) 5.36 ng·mL, and extensive metabolizer 10.65 ng·mL, P < 0.01). Median plasma levels of TAM (161.50 ng·mL) and HTF (1.32 ng·mL) in CYP2D6 IM/CYP3A4 poor metabolizer patients were higher (P < 0.05) than those from CYP2D6 IM/CYP3A4 extensive metabolizer patients (122.07 ng·mL and 0.61 ng·mL, respectively). Seasons contributed to the interpatient variability of EDF and HTF levels; summer concentrations were 24% and 42% higher compared with winter. Vitamin D3 was not associated to CYP3A4 metabolic activity, indicating that other mechanisms might be involved in the relation between TAM metabolism and vitamin D exposure. CYP3A4 contributes to the bioactivation of TAM through formation of HTF and becomes increasingly important in case of reduced or absent CYP2D6 activity. EDF and HTF exposure were associated to seasonal variations, with considerable higher plasma concentrations during summer.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
25-Hydroxyvitamin D3 solution, 100 μg/mL in ethanol, 98% (CP)
Sigma-Aldrich
25-Hydroxyvitamin D3 solution, 5 μg/mL in ethanol, 98% (CP)
Sigma-Aldrich
25-Hydroxyvitamin D3 solution, 50 μg/mL in ethanol, 98% (CP)
Sigma-Aldrich
25-Hydroxyvitamin D3 monohydrate, ≥99.0% (HPLC)
Sigma-Aldrich
25-Hydroxycholecalciferol, ≥98% (HPLC)
Supelco
25-Hydroxyvitamin D3 solution, 100 μg/mL in ethanol, ampule of 1 mL, certified reference material, Cerilliant®