435 results match your criteria Tamoxifen Metabolism and CYP2D6


Hepatic Models in Precision Medicine: An African Perspective on Pharmacovigilance.

Front Genet 2022 14;13:864725. Epub 2022 Apr 14.

Bioengineering and Integrated Genomics Group, Next Generation Health Cluster, Council for Scientific and Industrial Research, Pretoria, South Africa.

Pharmaceuticals are indispensable to healthcare as the burgeoning global population is challenged by diseases. The African continent harbors unparalleled genetic diversity, yet remains largely underrepresented in pharmaceutical research and development, which has serious implications for pharmaceuticals approved for use within the African population. Adverse drug reactions (ADRs) are often underpinned by unique variations in genes encoding the enzymes responsible for their uptake, metabolism, and clearance. Read More

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(Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study.

J Pers Med 2022 Mar 22;12(4). Epub 2022 Mar 22.

Post Graduation Department, Pontifical Catholic University of Parana, Curitiba 80215-901, Brazil.

Adherence to treatment and use of co-medication, but also molecular factors such as CYP2D6 genotype, affect tamoxifen metabolism, with consequences for early breast cancer prognosis. In a prospective study of 149 tamoxifen-treated early-stage breast cancer patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinico-pathological factors. Twenty-five patients (16. Read More

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Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment.

Ther Adv Med Oncol 2022 17;14:17588359221081075. Epub 2022 Mar 17.

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Introduction: In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid.

Methods: We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Read More

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A Clinical Review on Paroxetine and Emerging Therapies for the Treatment of Vasomotor Symptoms.

Int J Womens Health 2022 10;14:353-361. Epub 2022 Mar 10.

Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA.

Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some women choose not to use HT or have contraindications to using HT. Non-hormonal treatment options should be offered to these symptomatic menopausal women. Read More

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Design and implementation of a novel pharmacogenetic assay for the identification of the CYP2D6*10 genetic variant.

BMC Res Notes 2022 Mar 16;15(1):104. Epub 2022 Mar 16.

Department of Anatomy, Genetics and Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.

Objectives: Tamoxifen is considered to be the most widely used adjuvant therapy for hormone receptor positive breast cancer in premenopausal women. However, it is reported that nearly 30% of patients receiving tamoxifen therapy have shown reduced or no benefits. This may be due to the high inter-individual variations in the CYP2D6 gene that is involved in tamoxifen metabolism. Read More

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Inhibition of Cytochrome P450s by Strobilanthes crispus Sub-Fraction (F3): Implication for Herb-Drug Interaction.

Eur J Drug Metab Pharmacokinet 2022 May 11;47(3):431-440. Epub 2022 Feb 11.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia.

Background And Objective: Strobilanthes crispus Blume sub-fraction (F3) has been reported to be cytotoxic against cancer cells and to cause murine mammary tumor regression. Potential utilization of F3 as an adjuvant in breast cancer treatment to alleviate chemotherapeutic drug resistance is currently hampered by potential cytochrome P450 (CYP)-mediated herb-drug interactions (HDIs). The current study assessed the inhibitory potency of F3 towards five CYP enzymes involved in tamoxifen metabolism. Read More

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Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER-positive and Triple-Negative Breast Cancer Cell Lines.

ChemMedChem 2022 04 17;17(7):e202100720. Epub 2022 Feb 17.

Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, 11835, Cairo, Egypt.

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Read More

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Comparison of adverse drug reactions between tamoxifen and toremifene in breast cancer patients with different CYP2D6 genotypes: A propensity-score matched cohort study.

Int J Cancer 2022 05 12;150(10):1664-1676. Epub 2022 Jan 12.

Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

CYP2D6 gene polymorphism has a profound impact upon the effect of tamoxifen as adjuvant endocrine therapy in breast cancer. However, it had never been reported whether the adverse drug reactions vary by CYP2D6 metabolic status for patients treated with tamoxifen or toremifene. We conducted a retrospective study in breast cancer patients to investigate the impact of CYP2D6 metabolic status on liver dysfunction events, gynecological events and dyslipidemia events. Read More

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Evaluating the Risk of Breast Cancer Recurrence and Metastasis After Adjuvant Tamoxifen Therapy by Integrating Polymorphisms in Cytochrome P450 Genes and Clinicopathological Characteristics.

Front Oncol 2021 19;11:738222. Epub 2021 Nov 19.

Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Tamoxifen (TAM) is the most commonly used adjuvant endocrine drug for hormone receptor-positive (HR+) breast cancer patients. However, how to accurately evaluate the risk of breast cancer recurrence and metastasis after adjuvant TAM therapy is still a major concern. In recent years, many studies have shown that the clinical outcomes of TAM-treated breast cancer patients are influenced by the activity of some cytochrome P450 (CYP) enzymes that catalyze the formation of active TAM metabolites like endoxifen and 4-hydroxytamoxifen. Read More

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November 2021

DEHP mediates drug resistance by directly targeting AhR in human breast cancer.

Biomed Pharmacother 2022 Jan 18;145:112400. Epub 2021 Nov 18.

Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Resistance to chemotherapy and hormonal therapy is a major clinical problem in breast cancer medicine, especially for cancer metastasis and recurrence. Di(2-ethylhexyl)phthalate (DEHP) affects drug resistance by an unknown mechanism of action. Here we analyzed breast cancer patients (N = 457) and found that ΣMEHP (the sum of MEHP, MEHHP, MECPP and MEOHP concentrations) in urine was significantly higher (P = 0. Read More

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January 2022

Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer.

Clin Pharmacokinet 2022 04 17;61(4):527-537. Epub 2021 Nov 17.

Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Background: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14-16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5. Read More

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Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside.

Endocrinology 2021 12;162(12)

Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. Read More

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December 2021

Toward predicting CYP2D6-mediated variable drug response from gene sequencing data.

Sci Transl Med 2021 07;13(603)

Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.

Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Read More

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Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites.

J Pers Med 2021 Jun 4;11(6). Epub 2021 Jun 4.

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA.

Background: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with activity. Associations of tamoxifen efficacy with measured or -predicted endoxifen concentrations have been inconclusive. Read More

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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 Aug 29;77(8):1095-1111. 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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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 2022 Apr 15;35(2):322-326. 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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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 05 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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Predicting steady-state endoxifen plasma concentrations in breast cancer patients by CYP2D6 genotyping or phenotyping. Which approach is more reliable?

Pharmacol Res Perspect 2020 10;8(5):e00646

Clinical Pharmacology Unit of the Department of Medicine (DIMED), University of Padova, Padova, Italy.

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. Read More

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October 2020

Endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment.

Pharmacogenomics 2020 08 18;21(13):929-943. Epub 2020 Aug 18.

Unidad de Investigación Biomédica, 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, Mérida, Yucatán, 97150, México.

To evaluate plasma endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. A total of 138 breast cancer patients under tamoxifen treatment were cross-sectionally evaluated and side effects (SE) were recorded. genetic phenotypes (GP) and metabolic phenotypes (MP) were assessed (metabolic poor [mPM], intermediate [mIM], normal [mNM], and ultrarapid [mUM] metabolizer). Read More

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Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

J Hum Genet 2021 Feb 5;66(2):139-149. Epub 2020 Aug 5.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Read More

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February 2021

DNA derived from archival tumor specimens can be used for germline pharmacogenetic analyses.

Pharmacogenomics 2020 08 29;21(13):899-902. Epub 2020 Jul 29.

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

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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 03 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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