416 results match your criteria Tamoxifen Metabolism and CYP2D6


Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer.

J Pers Med 2021 Mar 13;11(3). Epub 2021 Mar 13.

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA.

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. Read More

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Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial.

NPJ Breast Cancer 2021 Mar 25;7(1):34. Epub 2021 Mar 25.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9-16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Read More

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Pharmacogenetics of tamoxifen therapy in Asian populations: from genetic polymorphism to clinical outcomes.

Eur J Clin Pharmacol 2021 Jan 29. Epub 2021 Jan 29.

College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China.

Background: Compared with western countries, Asian breast cancer patients have unique pathological and biological characteristics. Most of them are premenopausal women with HR positive. Tamoxifen as the first-line drug for premenopausal women with HR+ is involved in multiple enzymes and transporters during metabolizing and transporting process. Read More

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January 2021

Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse.

Sci Rep 2021 01 11;11(1):415. Epub 2021 Jan 11.

Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. Read More

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January 2021

Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics.

Expert Opin Drug Metab Toxicol 2021 Mar 29;17(3):307-321. Epub 2020 Dec 29.

Department of Pharmacology, Charles University and General University Hospital, Prague, Czech Republic.

: Tamoxifen is still an important drug in hormone-dependent breast cancer therapy. Personalization of its clinical use beyond hormone receptor positivity could improve the substantial variability of the treatment response.: The overview of the current evidence for the treatment personalization using therapeutic drug monitoring, or using genetic biomarkers including CYP2D6 is provided. Read More

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Reduction in Tamoxifen Metabolites Endoxifen and N-desmethyltamoxifen With Chronic Administration of Low Dose Cannabidiol: A CYP3A4 and CYP2D6 Drug Interaction.

J Pharm Pract 2020 Nov 15:897190020972208. Epub 2020 Nov 15.

Michael G. DeGroote Pain Clinic, 152969McMaster University Medical Centre, Hamilton, Ontario, Canada.

Background: Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date.

Case: A 58-year-old female with a history of bilateral breast carcinoma in remission, was treated with tamoxifen for breast cancer prevention for over 6 years. Read More

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November 2020

Simplified phenotyping of CYP2D6 for tamoxifen treatment using the N-desmethyl-tamoxifen/ endoxifen ratio.

Breast 2020 Dec 21;54:229-234. Epub 2020 Oct 21.

Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia; Sydney Medical School, University of Sydney, Camperdown, Australia; Macquarie University, Australia.

Introduction: CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. Read More

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December 2020

Model-Based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Clin Pharmacol Ther 2021 May 10;109(5):1244-1255. Epub 2020 Nov 10.

Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Read More

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Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

Br J Clin Pharmacol 2021 Mar 9;87(3):1243-1252. Epub 2020 Aug 9.

Department of Laboratory Medicine, Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Aims: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects.

Methods: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Read More

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does not impact on breast cancer-free survival in Southeast Mexican patients under tamoxifen treatment.

Per Med 2020 07 26;17(4):261-270. Epub 2020 Jun 26.

Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad, Hospital de Especialidades del Centro Médico Nacional 'Ignacio García Téllez', Instituto Mexicano del Seguro Social, Calle 41 No. 439, Col. Industrial, 97150 Mérida, Yucatán, México.

We conducted a retrospective analysis in 71 Mexican Mestizo patients to evaluate the breast cancer-free survival (BCFS) among the inferred genetic phenotypes (GP) of . was genotyped through Taqman-probe analysis; GP were inferred according to international guidelines. The BCFS was estimated through Kaplan-Meier method and analyzed with a log-rank test; hazard ratios were calculated with 95% CI and p < 0. Read More

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Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach.

Clin Pharmacol Ther 2020 09 23;108(3):661-670. Epub 2020 Jul 23.

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. Read More

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September 2020

Pharmacogenomics of breast cancer: highlighting CYP2D6 and tamoxifen.

J Cancer Res Clin Oncol 2020 Jun 8;146(6):1395-1404. Epub 2020 Apr 8.

The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, 6/F Esther Lee Building, Hong Kong, China.

Purpose: To review recent pharmacogenomics studies on breast cancer patients undergoing tamoxifen therapy, highlighting how our knowledge on cytochrome P450 2D6 (CYP2D6) can help to guide the development of adjuvant therapies for these patients.

Methods: A comprehensive literature search was conducted. Articles reporting findings pertaining to the effect of CYP2D6 on the therapeutic efficacy of tamoxifen, those reporting how targeting CYP2D6 could inform tamoxifen-based therapy development, and those on the tamoxifen effects on cell lines and animal models were included in the review. Read More

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Sex steroid hormones differentially regulate CYP2D in female wild-type and CYP2D6-humanized mice.

J Endocrinol 2020 05;245(2):301-314

National Institutes of Health, National Cancer Institute, Laboratory of Metabolism, Bethesda, Maryland, USA.

The CYP2D subfamily catalyses the metabolism of about 25% of prescribed drugs, including the majority of antidepressants and antipsychotics. At present, the mechanism of hepatic CYP2D regulation remains largely unknown. This study investigated the role of sex steroid hormones in CYP2D regulation. Read More

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Tamoxifen-related endocrine symptoms in Chinese patients with breast cancer: Study protocol clinical trial (SPIRIT Compliant).

Medicine (Baltimore) 2020 Feb;99(8):e19083

The Nethersole School of Nursing, The Chinese University of Hong Kong, Hong Kong.

Background: Breast cancer is the most prevalent cancer in females and disease recurrence remains a significant problem. To prevent recurrence, tamoxifen is prescribed for at least 5 years. However, among patients who receive tamoxifen, individual responses are highly variable. Read More

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February 2020

Variations and expression features of CYP2D6 contribute to schizophrenia risk.

Mol Psychiatry 2020 Feb 11. Epub 2020 Feb 11.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown. Here, we analyze 1497 RNA-seq data in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Read More

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February 2020

Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 polymorphism and their biological evaluation on MCF-7 cell line.

Drug Dev Res 2020 06 9;81(4):444-455. Epub 2020 Jan 9.

Institute of Zoology, Faculty of Biology, Technische Universität Dresden, Dresden, Germany.

Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4-hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Read More

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Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients.

BMC Pharmacol Toxicol 2019 12 19;20(Suppl 1):81. Epub 2019 Dec 19.

Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Background: Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. Read More

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December 2019

Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study.

J Clin Oncol 2020 02 10;38(6):558-566. Epub 2019 Dec 10.

Keio University School of Medicine, Tokyo, Japan.

Purpose: In patients taking tamoxifen, the genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome.

Methods: Patients who needed first-line tamoxifen therapy were enrolled. Read More

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February 2020

CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer.

J Clin Oncol 2020 02 4;38(6):548-557. Epub 2019 Dec 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Purpose: To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer.

Patients And Methods: We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. Read More

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February 2020

Post-marketing assessment of generic tamoxifen in Brazilian breast cancer patients.

Basic Clin Pharmacol Toxicol 2020 May 4;126(5):432-436. Epub 2019 Dec 4.

Coordenação de Pesquisa, Instituto Nacional de Câncer and Rede Nacional de Farmacogenética, Rio de Janeiro, Brazil.

Generic formulations of tamoxifen are commonly prescribed to oestrogen receptor-positive breast cancer patients at the Brazilian National Cancer Institute (INCA). We carried out a post-marketing surveillance of the generic tamoxifen formulation in current use at INCA, by comparing plasma concentrations of the parent drug and metabolites obtained with the generic vs the reference formulation. Thirty patients participated in an open-label, bracketed protocol, comprising 3 successive phases of 30-32 days each: the generic formulation was used in phases 1 and 3 and the reference formulation in phase 2. Read More

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The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)-Endoxifen in Breast Cancer.

Clin Transl Sci 2020 03 9;13(2):284-292. Epub 2019 Nov 9.

Pontifical Catholic University of Parana, Curitiba, Brazil.

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)-endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (liquid-chromatography tandem mass spectrometry), adherence behavior (Morisky, Green, and Levine medication adherence scale), and cytochrome P450 2D6 (CYP2D6) and other pharmacogene polymorphisms (matrix-assisted laser-desorption-ionization time of flight) mass spectrometry, real-time polymerase chain reaction). Read More

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Cost-effectiveness Analysis of CYP2D6*10 Pharmacogenetic Testing to Guide the Adjuvant Endocrine Therapy for Postmenopausal Women with Estrogen Receptor Positive Early Breast Cancer in China.

Clin Drug Investig 2020 Jan;40(1):25-32

Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, 350001, China.

Background: A CYP2D6 gene polymorphism is related to the effect of tamoxifen treatment in patient with estrogen-receptor positive (ER) positive breast cancer and CYP2D6*10 T/T can lead to a poor prognosis in Asian patients. Although one-off pharmacogenetic testing may optimize adjuvant endocrine therapy, testing prior to tamoxifen initiation incurs additional costs.

Aim: We conducted a study to assess the cost-effectiveness of CYP2D6*10 pharmacogenetic testing to guide the adjuvant endocrine therapy compared with tamoxifen without CYP2D6*10 testing in China. Read More

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January 2020

Non- Variants Selected by a GWAS Improve the Prediction of Impaired Tamoxifen Metabolism in Patients with Breast Cancer.

J Clin Med 2019 Jul 24;8(8). Epub 2019 Jul 24.

Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.

A certain minimum plasma concentration of ()-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient ()-endoxifen exposure. A metabolic ratio (MR) corresponding to the ()-endoxifen efficacy threshold level was adopted as a cutoff value for a genome-wide association study comprised of 287 breast cancer patients. Read More

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Tamoxifen Pharmacogenetics and Metabolism: The Same Is Not the Same.

J Clin Oncol 2019 08 18;37(22):1981-1982. Epub 2019 Jun 18.

Hiltrud Brauch, PhD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany, and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Werner Schroth, PhD and Thomas Mürdter, PhD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tübingen, Tübingen, Germany; and Matthias Schwab, MD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany, and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

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Plasma endoxifen and 4-hydroxytamoxifen levels in CYP2D6(C100T) carrying breast cancer patients and association with serum cholesterol.

Toxicol Appl Pharmacol 2019 09 10;378:114619. Epub 2019 Jun 10.

National Research Institute of Chinese Medicine, Taipei, Taiwan; Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei, Taiwan; Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. Electronic address:

Breast cancer patients with high cholesterol biosynthesis signature had poorer therapeutic outcome. Cytochrome P450 (CYP) 2D6 is crucial in the oxidation of tamoxifen to generate active metabolites, 4-hydroxytamoxifen and endoxifen. CYP2D6 variants with C100T substitution encode null or poor functional proteins. Read More

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September 2019

Tamoxifen-induced severe hot flashes and endoxifen levels: is dose reduction a safe and effective strategy?

Breast 2019 Aug 6;46:52-57. Epub 2019 May 6.

Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.

Objectives: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. Read More

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Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen.

Expert Rev Clin Pharmacol 2019 Jun 30;12(6):523-536. Epub 2019 Apr 30.

a Leiden Network for Personalised Therapeutics , Leiden University Medical Center , Leiden , The Netherlands.

: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Read More

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Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen.

Cancers (Basel) 2019 Mar 22;11(3). Epub 2019 Mar 22.

Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Read More

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Association of CYP2D6*10 (c. 100 C>T) Genotype with Z-END Concentration in Patients with Breast Cancer Receiving Tamoxifen Therapy in Indonesian Population.

Endocr Metab Immune Disord Drug Targets 2019 ;19(8):1198-1206

Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.

Background: Tamoxifen (TAM) is a frequently used hormonal prodrug for patients with breast cancer that needs to be activated by cytochrome P450 2D6 (CYP2D6) into Zusammen-endoxifen (Z-END).

Objective: The purpose of the study was to determine the association between CYP2D6*10 (c.100C>T) genotype and attainment of the plasma steady-state Z-END minimal threshold concentration (MTC) in Indonesian women with breast cancer. Read More

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Dynamic Effects of CYP2D6 Genetic Variants in a Set of Poor Metaboliser Patients with Infiltrating Ductal Cancer Under Treatment with Tamoxifen.

Sci Rep 2019 02 21;9(1):2521. Epub 2019 Feb 21.

Universidad Simón Bolivar, Facultad de Ciencias Básicas y Biomédicas, Laboratorio de Simulación Molecular y Bioinformática, Barranquilla, 080002, Colombia.

Breast cancer is a group of multigenic diseases. It is the most common cancer diagnosed among women worldwide and is often treated with tamoxifen. Tamoxifen is catalysed by cytochrome P450 2D6 (CYP2D6), and inter-individual variations in the enzyme due to single nucleotide polymorphisms (SNPs) could alter enzyme activity. Read More

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February 2019