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Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study

Abstract : In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)-pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single-nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (P < 0.0001), CYP3A4*22 genotype (P = 0.0003), and concomitant intake of potent CYP2D6 inhibitors (P < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping intermediate metabolizer (IM)/IM and IM/poor metabolizer diplotype into IM phenotype for future use in tamoxifen therapy optimization. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A4*22, CYP2C19*2, and CYP2B6*6 genetic polymorphisms.
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https://hal.umontpellier.fr/hal-02420919
Contributeur : Anthony Herrada <>
Soumis le : vendredi 20 décembre 2019 - 10:51:02
Dernière modification le : dimanche 25 octobre 2020 - 07:04:24

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Alicja Puszkiel, Cécile Arellano, Christelle Vachoux, Alexandre Evrard, Valérie Le Morvan, et al.. Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study. Clinical Pharmacology and Therapeutics, American Society for Clinical Pharmacology and Therapeutics, 2019, 106 (3), pp.585-595. ⟨10.1002/cpt.1404⟩. ⟨hal-02420919⟩

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