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Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma
Author(s) -
Mürdter TE,
Schroth W,
BacchusGerybadze L,
Winter S,
Heinkele G,
Simon W,
Fasching PA,
Fehm T,
Eichelbaum M,
Schwab M,
Brauch H
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.27
Subject(s) - cyp2d6 , tamoxifen , active metabolite , cyp2b6 , metabolite , chemistry , cyp2c9 , cyp2c19 , estrogen , estrogen receptor , pharmacology , cytochrome p450 , pharmacogenetics , pharmacokinetics , endocrinology , medicine , cyp3a4 , enzyme , genotype , biology , breast cancer , biochemistry , cancer , gene
The therapeutic effect of tamoxifen depends on active metabolites, e.g., cytochrome P450 2D6 (CYP2D6) mediated formation of endoxifen. To test for additional relationships, 236 breast cancer patients were genotyped for CYP2D6 , CYP2C9 , CYP2B6 , CYP2C19 , CYP3A5 , UGT1A4 , UGT2B7 , and UGT2B15 ; also, plasma concentrations of tamoxifen and 22 of its metabolites, including the (E)‐, (Z)‐, 3‐, and 4′‐hydroxymetabolites as well as their glucuronides, were quantified using liquid chromatography–tandem mass spectrometry (MS). The activity levels of the metabolites were measured using an estrogen response element reporter assay; the strongest estrogen receptor inhibition was found for (Z)‐endoxifen and (Z)‐4‐hydroxytamoxifen (inhibitory concentration 50 (IC50) 3 and 7 nmol/l, respectively). CYP2D6 genotypes explained 39 and 9% of the variability of steady‐state concentrations of (Z)‐endoxifen and (Z)‐4‐hydroxytamoxifen, respectively. Among the poor metabolizers, 93% had (Z)‐endoxifen levels below IC90 values, underscoring the role of CYP2D6 deficiency in compromised tamoxifen bioactivation. For other enzymes tested, carriers of reduced‐function CYP2C9 (*2, *3) alleles had lower plasma concentrations of active metabolites ( P < 0.004), pointing to the role of additional pathways. Clinical Pharmacology & Therapeutics (2011) 89 5, 708–717. doi: 10.1038/clpt.2011.27