Endoxifen Levels and Its Association With CYP2D6 Genotype and Phenotype

Antunes, Marina Venzon; Linden, Rafael; Santos, Tamyris V.; Wallemacq, Pierre; Haufroid, Vincent; Classen, Jean-François; Andreolla, Huander Felipe; Costa, Nathalia Cruz da; Fontanive, Tiago Oselame; Rosa, Daniela Dornelles

doi:10.1097/ftd.0b013e318260b46e

Cited by 31 publications

(25 citation statements)

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“…The amplitude of concentrations may be attributed to the interindividual pharmacokinetic variability, including polymorphisms of CYP2D6 and CYP3A4 and drugs interactions [1,2,[4][5][6][7]. Thus, we evaluated the impact of CYP2D6 inhibitors on EDF levels and [NDT]/[EDF] metabolic ratio in both matrices and found reduced metabolites concentrations in patients under concomitant use of CYP2D6 inhibitors drug inhibitors (Table 4) as compared to the group without use of drug inhibitors, as follows: median DBS 3.5 ng mL À 1 vs 5.8 ng mL À 1 , EPC 6.1 ng mL À 1 vs 10.2 ng mL À 1 and measured plasma 5.5 ng mL À 1 vs 10.1 ng mL À 1 (Po 0.05 in DBS and EPC, and Po 0.01 in measured plasma).…”

Section: Clinical Application and Methods Comparisonmentioning

confidence: 99%

“…These findings, along with the increasing knowledge about TAM metabolism modulating agents, encouraged studies with individualized dose adjustments, with increased doses for patients with impaired EDF formation (30 or 40 mg day À 1 ) [9][10][11]. Moreover, the metabolic ratio [NDF]/[EDF] has been described as an appropriate surrogate of CYP2D6 activity, rendering useful clinical information about TAM metabolism [5]. Considering the available evidence, therapeutic drug monitoring of TAM and its main metabolites during hormonal therapy of breast cancer could be an important tool to obtain optimal pharmacological response, recognizing patients eligible to higher TAM doses or alternative pharmacotherapy.…”

Section: Introductionmentioning

confidence: 94%

“…CYP2D6 also catalyzes the metabolism of TAM to 4-hydroxy-TAM (HTF) [4]. The antiestrogenic activity of TAM is mainly due to EDF, which, as HTF, is up to 100 times more potent to inhibit the proliferation of Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/talanta estrogen-dependent cells, and usually have plasma concentrations up to 6 times higher than HTF [5].…”

Section: Introductionmentioning

confidence: 99%

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Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Antunes

Raymundo

Oliveira

et al. 2015

Talanta

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A LC-MSMS method for the simultaneous determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots samples was developed and validated. The method employs an ultrasound-assisted liquid extraction and a reversed phase separation in an Acquity(®) C18 column (150×2.1 mm, 1.7 µm). Mobile phase was a mixture of formic acid 0.1% (v/v) pH 2.7 and acetonitrile (gradient from 60:40 to 50:50, v/v). Total analytical run time was 8 min. Precision assays showed CV % lower than 10.75% and accuracy in the range 94.5 to 110.3%. Mean analytes recoveries from DBS ranged from 40% to 92%. The method was successfully applied to 91 paired clinical DBS and plasma samples. Dried blood spots concentrations were highly correlated to plasma, with rs>0.83 (P<0.01). Median estimated plasma concentrations after hematocrit and partition factor adjustment were: TAM 123.3 ng mL(-1); NDT 267.9 ng mL(-1), EDF 10.0 ng mL(-1) and HTF 1.3 ng mL(-1,) representing in average 98 to 104% of the actually measured concentrations. The DBS method was able to identify 96% of patients with plasma EDF concentrations below the clinical threshold related to better prognosis (5.9 ng mL(-1)). The procedure has adequate analytical performance and can be an efficient tool to optimize adjuvant breast cancer treatment, especially in resource limited settings.

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Section: Clinical Application and Methods Comparisonmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Antunes

Raymundo

Oliveira

et al. 2015

Talanta

Self Cite

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“…The most common PM allele in this ethnic group is CYP2D6*4 , which is responsible for 75% of European PMs (15). Other null alleles, also present in Caucasians, are represented by the polymorphic alleles *3 , *5 , and *6 (16).…”

Section: Introductionmentioning

confidence: 99%

Determination of CYP2D6 3, 4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival

Martins

Vidal

Souza

et al. 2014

Braz J Med Biol Res

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The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14.4%). The *3 allele was not present in the studied population, and *4 had an allelic frequency of 0.13 (13.8%). We conclude that patients with reduced CYP2D6 activity did not present worse tumor characteristics or decreased disease-free survival than women with normal enzyme activity, as the difference was not statistically significant. We also observed a high frequency of CYP2D6 *10, which had not been previously described in this specific population. This study is the first in north-northeastern Brazil that aimed to contribute to the knowledge of the Brazilian regional profile for CYP2D6 polymorphisms and their phenotypes. These findings add to the knowledge of the distribution of different polymorphic CYP2D6 alleles and the potential role of CYP2D6 genotyping in clinical practice prior to choosing therapeutic protocols.

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“…Allele frequency differs among populations, resulting in phenotypic differences including altered drug metabolism [25,26,27]. Thus, genetic variation is a significant determinant of the efficacy and side effect profile of tamoxifen.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Endometrial Thickness and Bone Mineral Density Based on CYP2D6 Polymorphisms in Turkish Breast Cancer Patients Receiving Tamoxifen Treatment

Günaldı

Erkisi²,

Afşar³

et al. 2014

Pharmacology

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Background: Several previous studies have examined the effect of CYP2D6 gene polymorphism on the efficacy and metabolism of tamoxifen (Tamoxifen Teva, Nolvadex) in the treatment of breast cancer. In the present study, the metabolic profiles associated with various CYP2D6 genotypes were evaluated. Method: In the present study 92 Turkish breast cancer patients with early-stage hormone receptor-positive tumors treated with adjuvant tamoxifen (20 mg) were evaluated for CYP2D6 genotype and metabolic profiles. Known side effects of tamoxifen treatment, including endometrial thickening, changes in serum lipid levels and bone density, and hepatosteatosis, were evaluated according to the CYP2D6 polymorphism. Result: The distribution of metabolic characteristics in the Turkish population was as follows: 77.1% normal metabolism, 11.5% intermediate metabolism, 5.2% ultrarapid metabolism, and 2.1% poor metabolism. The CYP2D6 genotypes associated with rapid metabolism were CYP2D6 3X*1/*1 duplication (DUP) and CYP2D6 2X*1/*2, while poor metabolism was associated with the genotypes CYP2D6 *3/*4 and CYP2D6 *6/*6. There was no statistically significant relationship between metabolic characteristics and bone density or hepatosteatosis. A statistically significant difference in total cholesterol and triglycerides was detected in lipid profile analysis (p = 0.003, p = 0.02). Assessment of endometrial thickness revealed a significant association of hyperplasia and poor metabolism, and an association between atrophy and ultrarapid metabolism (p = 0.01). Conclusion: Significant development of endometrial hyperplasia was identified among individuals with poor tamoxifen metabolism. As a result, tamoxifen may be a significant predictor of endometrial thickening among individuals with poor metabolic characteristics.

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Endoxifen Levels and Its Association With CYP2D6 Genotype and Phenotype

Abstract: CYP2D6 genotyping and/or phenotyping could not fully predict EDF concentrations. Monitoring EDF itself could be considered during TAM therapy.

Cited by 31 publications

References 35 publications

Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Determination of CYP2D6 3, 4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival

Evaluation of Endometrial Thickness and Bone Mineral Density Based on CYP2D6 Polymorphisms in Turkish Breast Cancer Patients Receiving Tamoxifen Treatment

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Endoxifen Levels and Its Association With CYP2D6 Genotype and Phenotype

Abstract: CYP2D6 genotyping and/or phenotyping could not fully predict EDF concentrations. Monitoring EDF itself could be considered during TAM therapy.

Cited by 31 publications

References 35 publications

Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N -desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots—Development, validation and clinical application during breast cancer adjuvant therapy

Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival

Evaluation of Endometrial Thickness and Bone Mineral Density Based on CYP2D6 Polymorphisms in Turkish Breast Cancer Patients Receiving Tamoxifen Treatment

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Determination of CYP2D6 3, 4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival