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Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age
Author(s) -
Desta Z,
Kreutz Y,
Nguyen A T,
Li L,
Skaar T,
Kamdem L K,
Henry N L,
Hayes D F,
Storniolo A M,
Stearns V,
Hoffmann E,
Tyndale R F,
Flockhart D A
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.2011.174
Subject(s) - letrozole , cyp2a6 , medicine , breast cancer , exemestane , pharmacogenomics , pharmacogenetics , body mass index , pharmacology , oncology , aromatase inhibitor , endocrinology , aromatase , genotype , cancer , biology , genetics , metabolism , cyp1a2 , gene , cytochrome p450
The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned ( n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro . DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes ( P < 0.0001), body mass index (BMI) ( P < 0.0001), and age ( P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo . CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects. Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi: 10.1038/clpt.2011.174