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J Clin Oncol 2019 Jan 24:JCO1800307. Epub 2019 Jan 24.

1 Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5. Read More

BMC Complement Altern Med 2019 Jan 18;19(1):23. Epub 2019 Jan 18.

Society for Cancer Research, Hiscia Institute, Arlesheim, Switzerland.

Background: Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. Especially in Europe, breast cancer patients use herbal products containing mistletoe (Viscum album L.). Read More

Cancer Causes Control 2019 Jan 12;30(1):103-112. Epub 2018 Dec 12.

University of Washington, Seattle, WA, USA.

Purpose: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen. Read More

Breast Cancer Res 2018 12 10;20(1):149. Epub 2018 Dec 10.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. Read More

PLoS One 2018 22;13(8):e0202534. Epub 2018 Aug 22.

Molecular Modeling Group, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

Characterization of cytochrome P450 2D6 (CYP2D6) and the impact of the major identified allelic variants on the activity of one of the most dominating drug-metabolising enzymes is essential to increase drug safety and avoid adverse reactions. Microsecond molecular dynamics simulations have been performed to capture the dynamic signatures of this complex enzyme and five allelic variants with diverse enzymatic activity. In addition to the apo simulations, three substrates (bufuralol, veliparib and tamoxifen) and two inhibitors (prinomastat and quinidine) were included to explore their influence on the structure and dynamical features of the enzyme. Read More

Breast Cancer Res Treat 2018 Nov 17;172(2):401-411. Epub 2018 Aug 17.

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

Purpose: Tamoxifen has a wide inter-variability. Recently, two SNPs in the 3'-untranslated region (UTR) of the SULT1A1 gene, rs6839 and rs1042157, have been associated with decreased SULT1A1 activity. The aim of this study is to investigate the role of the rs6839 and rs1042157 on tamoxifen metabolism and relapse-free survival (RFS) in women diagnosed with early-breast cancer receiving tamoxifen. Read More

Pharmacogenomics 2018 Aug 19;19(13):1027-1037. Epub 2018 Jul 19.

Department of Oncology & Pathology, Karolinska Institutet, SE171-76 Stockholm, Sweden.

Aim: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients.

Materials & Methods: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival.

Results & Conclusion: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑-2D6↓ (hazard ratio: 2. Read More

Breast Cancer Res Treat 2018 Oct 6;171(3):701-708. Epub 2018 Jul 6.

Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, N6A 5K5, Canada.

Purpose: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. Read More

Eur J Drug Metab Pharmacokinet 2018 Oct;43(5):495-508

Professor Emeritus, School of Pharmacy, University of Washington, Seattle, WA, 98195, USA.

Tamoxifen is a prodrug, and most of the therapeutic effect in treating breast cancer stems from its metabolite, endoxifen. Since cytochrome P450 (CYP) 2D6 is the most important enzyme in the production of endoxifen, drugs that inhibit CYP2D6 would be expected to reduce tamoxifen efficacy. In addition to drug-drug interactions (DDI) involving CYP2D6, there is growing evidence that enzyme inducers can substantially alter the disposition of endoxifen, reducing tamoxifen efficacy. Read More

Biol Pharm Bull 2018 May 14;41(5):722-732. Epub 2018 Feb 14.

Graduate School of Biomedical and Health Sciences, Hiroshima University.

Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Read More

Arch Toxicol 2018 Mar 28;92(3):1099-1112. Epub 2017 Dec 28.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376, Stuttgart, Germany.

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. Read More

Oncotarget 2017 Nov 1;8(59):100296-100311. Epub 2017 Nov 1.

Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea.

Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Read More

Breast Cancer Res 2017 Nov 28;19(1):125. Epub 2017 Nov 28.

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

Background: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Read More

Front Pharmacol 2017 24;8:582. Epub 2017 Aug 24.

Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgart, Germany.

Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. Read More

Pharmacogenet Genomics 2017 11;27(11):402-409

aDepartment of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan bUNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina cDeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida dDepartment of Clinical Pharmacology, Indiana University, Indianapolis, Indiana eBon Secours Cancer Institute, Richmond, Virginia, USA.

Objectives: Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations.

Patients And Methods: Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Read More

J Clin Oncol 2017 Oct 30;35(30):3391-3400. Epub 2017 Aug 30.

Matthew P. Goetz, Vera J. Suman, Joel M. Reid, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Mary Kuffel, Sarah A. Buhrow, Stephanie L. Safgren, Renee M. McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A. Adjei, Dan Visscher, Benjamin R. Kipp, Minetta C. Liu, John R. Hawse, Matthew M. Ames, and James N. Ingle, Mayo Clinic, Rochester, MN; Zachary R. Chalmers and Garrett Frampton, Foundation Medicine, Cambridge, MA; and John R. Hawse, James H. Doroshow, Jerry M. Collins, and Howard Streicher, National Cancer Institute, Bethesda, MD.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. Read More

Eur J Clin Pharmacol 2017 Dec 28;73(12):1589-1598. Epub 2017 Aug 28.

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

Background: Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Read More

Chem Biodivers 2018 Jan 28;15(1). Epub 2017 Dec 28.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, P. R., China.

Norendoxifen, an active metabolite of tamoxifen, is a potent aromatase inhibitor. Little information is available regarding production of norendoxifen in vitro. Here, we conducted a series of kinetic and inhibition studies in human liver microsomes (HLMs) and expressed P450s to study the metabolic disposition of norendoxifen. Read More

Anticancer Agents Med Chem 2017 ;17(13):1805-1813

Division of Chemical Pathology, Department of Pathology Faculty of Medicine and Health Sciences, Stellenbosch University and the National Health Laboratory Service, Tygerberg Hospital, Tygerberg. South Africa.

Background: Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures. Read More

Breast Cancer (Dove Med Press) 2017 6;9:111-120. Epub 2017 Mar 6.

Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.

Introduction And Aims: Tamoxifen is an adjuvant drug effective in treating hormone receptor - positive breast cancer. However, 30%-50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Read More

Oncotarget 2017 Mar;8(13):20925-20938

Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12. Read More

Klin Onkol 2016 ;29 Suppl 3:S29-38

Ovarian suppression or ovarian ablation used in treatment of breast carcinoma results in temporary or permanent menopause and associated menopausal symptoms - most frequently vasomotoric symptoms (hot flashes, sweats), vaginal atrophy, sleep disturbances. Patients can also experience frequent decrease in bone density (osteopenia, osteoporosis), mood swings or depression, less frequently cardiac toxicity. Managements of these symptoms is complex. Read More

Planta Med 2017 Apr 24;83(6):496-508. Epub 2017 Jan 24.

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Florida, USA.

This review summarizes published , animal, and clinical studies investigating the effects of green tea () extract and associated catechins on drug-metabolizing enzymes and drug transporters. studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Read More

Rev Med Chil 2016 Oct;144(10):1326-1335

Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Read More

Am J Epidemiol 2017 01 17;185(2):75-85. Epub 2016 Dec 17.

Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Read More

Drug Metab Dispos 2017 01 18;45(1):17-22. Epub 2016 Oct 18.

Division of Cancer Research, Level 9, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, United Kingdom

Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug-drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. Read More

Pharmacogenomics J 2017 03 4;17(2):109-111. Epub 2016 Oct 4.

Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain.

Am J Transl Res 2016 15;8(8):3585-92. Epub 2016 Aug 15.

Department of Medical Oncology, Zhejiang Cancer Hospital Hangzhou, Zhejiang Province, P. R. China.

Tamoxifen is the most widely used adjuvant endocrine therapy for breast cancer. However, the pharmacogenetic effect of CYP2D6 on its efficacy remains unclear. Therefore, this study aimed to evaluate the association of CYP2D6*10 (c. Read More

Curr Comput Aided Drug Des 2017 ;13(1):39-47

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria.

Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether.

Objective: This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination.

Method: Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates. Read More

PLoS One 2016 7;11(9):e0162361. Epub 2016 Sep 7.

Beijing Hospital, National Center of Gerontology, Beijing, China.

Tamoxifen has been successfully used for treating breast cancer and preventing cancer recurrence. Cytochrome P450 2D6 (CYP2D6) plays a key role in the process of metabolizing tamoxifen to its active moiety, endoxifen. Patients with variants of the CYP2D6 gene may not receive the full benefit of tamoxifen treatment. Read More

Yao Xue Xue Bao 2016 09;51(9):1356-67

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30- to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. Read More

Breast Cancer (Dove Med Press) 2016 8;8:149-55. Epub 2016 Aug 8.

Department of Pharmacy Practice, Faculty of Pharmaceutical Science.

Background: Tamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment. Read More

Drug Metab Dispos 2016 11 18;44(11):1736-1741. Epub 2016 Aug 18.

Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California.

Animals are not commonly used to assess drug-drug interactions due to poor clinical translatability arising from species differences that may exist in drug-metabolizing enzymes and transporters, and their regulation pathways. In this study, a transgenic mouse model expressing human pregnane X receptor (PXR), constitutive androstane receptor (CAR), CYP3A4/CYP3A7, and CYP2D6 (Tg-composite) was used to investigate the effect of induction mediated by rifampin on the pharmacokinetics of tamoxifen and its metabolites. In humans, tamoxifen is metabolized primarily by CYP3A4 and CYP2D6, and multiple-day treatment with rifampin decreased tamoxifen exposure by 6. Read More

Breast Cancer Res Treat 2016 08 2;159(1):97-108. Epub 2016 Aug 2.

Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.

Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. Read More

Eur J Gynaecol Oncol 2016 08;37(4):504-510

Background: The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The aim of the present study is to estimate the incidence of CYP2D6*4, in the Greek population and more precisely among females suffering from breast cancer. Read More

Hautarzt 2016 Sep;67(9):718-23

Labor für medizinische Mikrobiologie, Mölbis, Deutschland.

The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Read More

Oncologist 2016 07 25;21(7):795-803. Epub 2016 May 25.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Bon Secours Cancer Institute, Richmond, Virginia, USA

Background: Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races. Read More

J Clin Pharmacol 2016 12 21;56(12):1570-1581. Epub 2016 Jun 21.

Department of Pathology, University of Utah, Salt Lake City, UT, USA.

Tamoxifen is metabolically activated to 4-hydroxytamoxifen and endoxifen by cytochrome P450 (CYP). CYP phenotypes have been correlated to tamoxifen outcomes, but few have considered drug interactions or combinations of genes. Fewer still have considered ABCB1, which encodes P-glycoprotein and transports active tamoxifen metabolites. Read More

BMC Cancer 2016 05 11;16:304. Epub 2016 May 11.

Division of Clinical Pharmacology, Department of Medicine, 339 Windermere Road B9-130, London, ON, N6A 5A5, Canada.

Background: Tamoxifen, a common anti-estrogen breast cancer medication, is a prodrug that undergoes bioactivation via cytochrome P450 enzymes, CYP2D6 and to a lesser degree, CYP3A4 to form the active metabolite endoxifen. With an increasing use of oral anti-cancer drugs, the risk for drug-drug interactions mediated by enzyme inhibitors and inducers may also be expected to increase. Here we report the first case demonstrating a potent drug-drug interaction in a real-world clinical setting between tamoxifen and rifampin in a breast cancer patient being treated concurrently for ulcerative colitis. Read More

J Pharm Pharmacol 2016 Jun 25;68(6):819-25. Epub 2016 Apr 25.

Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Objectives: This study aimed to assess the catalytic characteristics of 24 CYP2D6 allelic isoforms found in Chinese Han population on the metabolism of tamoxifen in vitro.

Methods: Recombinant CYP2D6 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity towards tamoxifen. About 5-2500 μm tamoxifen was incubated for 30 min at 37 °C. Read More

Clin Pharmacokinet 2016 10;55(10):1239-1250

Clinical Pharmacology, SingHealth, Singapore, Singapore.

Tamoxifen (TAM) is an established endocrine treatment for all stages of oestrogen receptor (ER)-positive breast cancer. Its complex metabolism leads to the formation of multiple active and inactive metabolites. One of the main detoxification and elimination pathways of tamoxifen and its active metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen, is via glucuronidation catalysed by uridine 5'-diphospho-glucuronosyltransferases (UGTs). Read More

Pharmacol Res 2016 05 8;107:398-406. Epub 2016 Apr 8.

Clinical Pharmacology and Pharmacogenetics Unit, Department of Laboratory Medicine, University Hospital, Pisa, Italy.

The clinical usefulness of assessing the enzymatic activity of CYPD6 in patients taking tamoxifen had been longly debated. In favour of preemptive evaluation of phenotypic profile of patients is the strong pharmacologic rationale, being that the formation of endoxifen, the major and clinically most important metabolite of tamoxifen, is largely dependent on the activity of CYP2D6. This enzyme is highly polymorphic for which the activity is largely depending on genetics, but that can also be inhibited by a number of drugs, i. Read More

Pharmacogenomics 2016 04 4;17(6):573-82. Epub 2016 Apr 4.

Molecular Prospection and Bioinformatics Group (ProspecMol) - Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego 1235, 50670-901, Cidade Universitária, Recife, PE, Brazil.

Unlabelled: CYP2D6 is a high polymorphic enzyme from P450, responsible for metabolizing almost 25% of drugs. The distribution of different mutations among CYP2D6 alleles has been associated with poor, intermediate, extensive and ultra-metabolizers.

Aim: To evaluate how missenses mutations in CYP2D6*7 and CYP2D6*14A poor metabolizer alleles affect CYP2D6 stability and function. Read More

Adv Exp Med Biol 2016 ;882:191-215

Division of Hematology, Oncology, Department of Internal Medicine, University of Michigan Medical School, 48109, Ann Arbor, 6310 Cancer Center, 1500 E. Medical Center Dr.MI, USA.

Pharmacogenetics attempts to predict treatment response using a patient's "germline" genome as the biomarker of interest. This chapter on pharmacogenetic predictors of breast cancer response is divided into four sections. The first introduces readers to genetic variation and describes how variation in the germline genome can affect biology or pharmacology. Read More

Tidsskr Nor Laegeforen 2016 Mar 15;136(5):434-6. Epub 2016 Mar 15.

Future Med Chem 2016 22;8(3):249-56. Epub 2016 Feb 22.

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

Background: Tamoxifen (TAM) is metabolized to the more active 4-hydroxytamoxifen by CYP2D6 enzyme. Due to the genetic polymorphisms in CYP2D6, clinical outcomes of TAM treatment vary. Novel flexible TAM analogs with altered activation pathway were synthesized and were tested for their antiproliferative action on MCF-7 cell lines and their binding affinity for ERα and ERβ. Read More

Eur J Med Chem 2016 Apr 9;112:171-179. Epub 2016 Feb 9.

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

Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. Read More

Clin Cancer Res 2016 07 4;22(13):3164-71. Epub 2016 Feb 4.

Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia. Faculty of Medicine and Health Sciences, Macquarie University, Sydney Australia.

Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels.

Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Read More

J Chromatogr A 2016 Feb 11;1434:64-9. Epub 2016 Jan 11.

Headquarters of Research Centers, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. Electronic address:

Tamoxifen, a hormonal therapy drug against estrogen receptor-positive breast cancer, can be metabolized by cytochrome P450 enzymes such as CYP3A4 and CYP3A5, and converted to N-desmethyltamoxifen, which is subsequently, metabolized by CYP2D6 and inverted to form 4-hydroxy-N-desmethyltamoxifen (endoxifen). Conventional mass spectrometry (MS) analyses of tamoxifen and its metabolites require isotopic internal standards (ISs). In this study, endoxifen and N-desmethyltamoxifen amine groups were modified by reductive amination with formaldehyde-D2 to produce new metabolite molecules. Read More

Br J Clin Pharmacol 2016 06 8;81(6):1142-52. Epub 2016 Mar 8.

Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.

Aim: The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer.

Methods: Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Read More