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1.
Pharmacogenomics ; 21(13): 929-943, 2020 08.
Article in English | MEDLINE | ID: mdl-32808577

ABSTRACT

Aim: To evaluate plasma endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. Patients & methods: A total of 138 breast cancer patients under tamoxifen treatment were cross-sectionally evaluated and side effects (SE) were recorded. CYP2D6 genetic phenotypes (GP) and metabolic phenotypes (MP) were assessed (metabolic poor [mPM], intermediate [mIM], normal [mNM], and ultrarapid [mUM] metabolizer). Associations were tested in uni-multivariate models for endoxifen >5.9 ng/ml and for mNM + mUM MP. Results: The main SE was hot flashes (62%). Distribution of the CYP2D6 MP was 4.3% mPM; 14.5% mIM; 75.4% mNM; and 5.8% mUM. Endoxifen >5.9 ng/ml was partially associated with SE (p = 0.06); the mNM + mUM MP was associated with treatment time (p = 0.03). Conclusion: The endoxifen-associated factors in Mexican Mestizo patients remain inconclusive, although treatment time was associated with MP.


Subject(s)
Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Tamoxifen/analogs & derivatives , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cross-Sectional Studies , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Female , Genotype , Humans , Mexico , Middle Aged , Phenotype , Racial Groups/genetics , Tamoxifen/blood
2.
Vet Med Sci ; 6(4): 673-678, 2020 11.
Article in English | MEDLINE | ID: mdl-32558352

ABSTRACT

Neutrophils participate in innate immunity as the first line of host defence against microorganisms. However, persistent neutrophil activity and delayed apoptosis can be harmful to surrounding tissues; this problem occurs in diverse inflammatory diseases, including asthma-affected horses. Previous studies in horses with acute lung inflammation indicated that treatment with tamoxifen (TX), a selective oestrogen receptor modulator, produces a significant decrease in bronchoalveolar lavage fluid (BALF) neutrophil content. The aim of this study was to investigate the effect of tamoxifen and its metabolites (N-desmethyltamoxifen and endoxifen) on the mitochondrial membrane potential assay by flow cytometry, and the activation of effector caspase-3 through immunoblotting, in peripheral blood neutrophils obtained from healthy horses (n = 5). Results show that tamoxifen, N-desmethyltamoxifen and endoxifen depolarize the mitochondrial membrane and activate caspase-3 in healthy equine neutrophils in vitro. These findings suggest that tamoxifen and its metabolites may activate the intrinsic apoptotic pathway in equine neutrophils. However, more studies are necessary to further explore the signalling pathways of these drugs in the induction of apoptosis.


Subject(s)
Anti-Asthmatic Agents/pharmacology , Caspase 3/immunology , Horses/immunology , Immunity, Innate/drug effects , Mitochondrial Membranes/drug effects , Neutrophils/drug effects , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacology , Animals , Female , Flow Cytometry/veterinary , Immunoblotting/veterinary , Male , Mitochondrial Membranes/physiology , Neutrophils/immunology
3.
Basic Clin Pharmacol Toxicol ; 126(5): 432-436, 2020 May.
Article in English | MEDLINE | ID: mdl-31758654

ABSTRACT

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. Two blood samples were collected in the last 4 days of each phase, for LC-MS/MS quantification of tamoxifen and metabolites in plasma. The median plasma concentrations (ng/mL) for the reference formulation were as follows: tamoxifen, 135.0 (CI 95% 114.2-155.8); endoxifen, 35.3 (30.0-40.8); and 4-hydroxytamoxifen, 4.8 (4.2-5.4). The endoxifen/tamoxifen plasma concentration ratio was 0.27 (0.21-0.25). ANOVA detected no statistically significant difference in plasma concentrations of tamoxifen, metabolites or the endoxifen/tamoxifen ratio among the three phases. The genetic component (rGC) of the CYP2D6-mediated conversion of tamoxifen into endoxifen, estimated using the repeated drug administration procedure across the three phases, was 0.87, pointing to an important component of genetic variability. In conclusion, this first post-marketing surveillance trial of oncologic generic drugs carried out in Brazilian patients verified the switchability between the reference and the generic tamoxifen formulation currently used at our institution. The adopted bracketed protocol adds confidence to this conclusion and may serve as a frame for future trials of post-marketing assessment of other generic drug products.


Subject(s)
Breast Neoplasms/drug therapy , Drugs, Generic/administration & dosage , Tamoxifen/administration & dosage , Adult , Aged , Antineoplastic Agents, Hormonal/administration & dosage , Brazil , Breast Neoplasms/blood , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Female , Genotype , Humans , Middle Aged , Product Surveillance, Postmarketing , Tamoxifen/analogs & derivatives , Tamoxifen/blood
4.
Clin Transl Sci ; 13(2): 284-292, 2020 03.
Article in English | MEDLINE | ID: mdl-31573754

ABSTRACT

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). Adherence explained 47% of the variability of tamoxifen plasma concentrations (P < 0.001). Although CYP2D6 alone explained 26.4%, the combination with adherence explained 40% of (Z)-endoxifen variability at 12 months (P < 0.001). The influence of low adherence to not achieving relevant (Z)-endoxifen levels was highest in patients with noncompromised CYP2D6 function (relative risk 3.65; 95% confidence interval 1.48-8.99). As a proof-of-concept, we demonstrated that (Z)-endoxifen levels are influenced both by patient adherence to tamoxifen and CYP2D6, which is particularly relevant for patients with full CYP2D6 function.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Medication Adherence/statistics & numerical data , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/pharmacokinetics , Brazil , Breast Neoplasms/blood , Breast Neoplasms/genetics , Cytochrome P-450 CYP2D6/metabolism , Drug Monitoring/statistics & numerical data , Female , Humans , Middle Aged , Pharmacogenomic Testing/statistics & numerical data , Pharmacogenomic Variants , Self Report/statistics & numerical data , Tamoxifen/analogs & derivatives , Tamoxifen/blood , Tamoxifen/metabolism , Tamoxifen/pharmacokinetics , Young Adult
5.
BMC Pharmacol Toxicol ; 20(Suppl 1): 81, 2019 12 19.
Article in English | MEDLINE | ID: mdl-31852530

ABSTRACT

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. METHODS: TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35-50 years) or postmenopausal (n = 20; aged 60-79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays. RESULTS: Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [ß-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (- 8.585 ± 3.060, p = 0.008). CONCLUSION: The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value. TRIAL REGISTRATION: RBR-7tqc7k.


Subject(s)
Breast Neoplasms/metabolism , Postmenopause/metabolism , Premenopause/metabolism , Tamoxifen/analogs & derivatives , Tamoxifen/metabolism , Tamoxifen/therapeutic use , Adult , Aged , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP3A/genetics , Female , Humans , Middle Aged , Polymorphism, Single Nucleotide , Tamoxifen/blood
6.
Biomed Chromatogr ; 33(4): e4462, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30536934

ABSTRACT

To date, several methods for the quantification of tamoxifen and its metabolites have been developed, most of which employ liquid chromatography tandem-mass spectrometry (LC-MS/MS). These methods are highly sensitive and reproducible, but are also time-consuming and require expensive equipment; one of their main disadvantages is matrix ionization effects. A more viable option, particularly in developing countries, is high-performance liquid chromatography coupled with UV or fluorescence detection. We developed and validated a method for simultaneous quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen based on high-performance liquid chromatography with fluorescence detection in a reverse-phase column. The method is rapid (16 min plus 5 min of column re-equilibrium), accurate (80-100%) and precise (0.23-6.00%), and does not require any additional irradiation process. Sample pretreatment consists of protein precipitation with acetonitrile under alkaline conditions, employing only 200 µL plasma. The validated method's wide range allowed quantification of steady-state levels in patients under standard tamoxifen treatment (20 mg/day). This assay is ready for application in clinical studies and routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in healthcare institutions.


Subject(s)
Antineoplastic Agents, Hormonal/blood , Breast Neoplasms/drug therapy , Chromatography, High Pressure Liquid/methods , Spectrometry, Fluorescence/methods , Tamoxifen/blood , Antineoplastic Agents, Hormonal/chemistry , Antineoplastic Agents, Hormonal/therapeutic use , Drug Monitoring/methods , Female , Humans , Limit of Detection , Linear Models , Reproducibility of Results , Tamoxifen/analogs & derivatives , Tamoxifen/chemistry , Tamoxifen/therapeutic use
7.
Menopause ; 23(6): 638-44, 2016 06.
Article in English | MEDLINE | ID: mdl-27045700

ABSTRACT

OBJECTIVE: Ospemifene is an estrogen-receptor agonist/antagonist (also known as a selective estrogen-receptor modulator) that is FDA approved for the treatment of moderate-to-severe dyspareunia, a symptom of vulvovaginal atrophy, due to menopause. Preclinical and clinical data suggest that ospemifene may also have an effect on bone health in postmenopausal women. METHODS: Relevant articles, including cellular and preclinical studies and clinical trials written in English pertaining to ospemifene and bone health, were identified from a database search of PubMed (from its inception to June 2015) and summarized in this comprehensive review. RESULTS: In vitro data suggest that ospemifene may mediate a positive effect on bone through osteoblasts. Ospemifene effectively reduced bone loss and resorption in ovariectomized rats, with activity comparable to estradiol and raloxifene. Clinical data from three phase 1 or 2 clinical trials (2 placebo- and 1 raloxifene-controlled) found ospemifene 60 mg/d to have a positive effect on the biochemical markers for bone turnover in healthy, postmenopausal women with significant improvements relative to placebo and comparable to raloxifene. CONCLUSIONS: Ospemifene 60 mg/d may have a protective effect on the bone health of women being treated for dyspareunia. The initial clinical data for ospemifene follows a trend similar to raloxifene and bazedoxifene, suggesting that ospemifene may have bone-protective effects in postmenopausal women. However, additional rigorous clinical trials are necessary to confirm any positive effects ospemifene may have on vertebral fractures and bone mineral density in healthy and osteoporotic women.


Subject(s)
Bone and Bones/drug effects , Dyspareunia/drug therapy , Postmenopause , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/analogs & derivatives , Animals , Bone Density/drug effects , Bone Remodeling/drug effects , Bone Resorption/prevention & control , Controlled Clinical Trials as Topic , Female , Humans , Osteoblasts/drug effects , Osteoblasts/physiology , Osteoclasts/drug effects , Osteoclasts/physiology , Osteoporosis/prevention & control , Ovariectomy , Rats , Tamoxifen/therapeutic use
8.
Menopause ; 23(2): 129-37, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26382313

ABSTRACT

OBJECTIVE: Some selective estrogen receptor modulators (SERMs) have been associated with increased incidence of urinary incontinence and pelvic organ prolapse. This study explored the effects of five SERMs on the function and matrix components of the vagina and its supportive tissues. METHODS: Fifty-six rats were administered SERMs by oral gavage for 8 weeks (n = 8 for each SERM): raloxifene, tamoxifen, idoxifene, bazedoxifene at three different doses, and bazedoxifene with conjugated estrogens. Thirty-two rats were used as controls (n = 8 per group): sham operation (no ovariectomy), ovariectomy only, ovariectomy with vehicle gavage, and 17ß-estradiol (subcutaneous). Vaginal supportive tissue complex was tested by uniaxial tensile testing. Total collagen content (hydroxyproline) and glycosaminoglycan content (Blyscan) were measured. RESULTS: Ovariectomy significantly decreased the mechanical integrity of the vagina and its supportive tissue complex, with a decrease in ultimate load and stiffness (all P < 0.05). Although 17ß-estradiol supplementation maintained these properties similarly to sham operation, none of the SERMs was as effective--particularly idoxifene, bazedoxifene at higher doses, and bazedoxifene with conjugated estrogens (all P < 0.05). In addition, idoxifene and bazedoxifene induced increased total collagen content compared with sham or 17ß-estradiol treatment (all P < 0.05). Glycosaminoglycan content did not change significantly. CONCLUSIONS: Unlike 17ß-estradiol, SERM supplementation does not fully prevent ovariectomy-induced deterioration in the biomechanical properties of the vagina and its supportive tissues, with the effects of idoxifene and bazedoxifene being the least. The paradoxically increased collagen content in these two groups may be related to increased formation of nonfunctional collagen.


Subject(s)
Collagen/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Vagina/drug effects , Animals , Dose-Response Relationship, Drug , Estrogens, Conjugated (USP)/pharmacology , Female , Indoles/pharmacology , Mammary Glands, Animal/drug effects , Raloxifene Hydrochloride/pharmacology , Random Allocation , Rats , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacology , Vagina/pathology
9.
Pharmacogenomics ; 16(6): 601-17, 2015.
Article in English | MEDLINE | ID: mdl-25893704

ABSTRACT

AIM: To evaluate the impact of CYP3A4*22 in the formation of endoxifen (EDF) and hydroxytamoxifen (HTF), under different CYP2D6 genotypic backgrounds. MATERIALS & METHODS: 178 patients were enrolled in the study. CYP2D6 and CYP3A4 genotyping and tamoxifen (TAM) and metabolites quantification were performed. RESULTS: EDF concentrations were lower in poor (2.77 ng ml(-1)) and CYP2D6 intermediate metabolizers (5.84 ng ml(-1)), comparing to functional group (EM-F) (10.67 ng ml(-1), p < 0.001). HTF and TAM levels were respectively 47 and 53% higher in CYP3A4*22 carriers compared with *1/*1 patients in the whole group. Patients with impaired CYP2D6 metabolism and carriers of CYP3A4*22 had EDF levels comparable to CYP2D6 EM-F group (9.06 and 10.67 ng ml(-1), p = 0.247). CONCLUSION: The presence of CYP3A4*22 might compensate the reduction of EDF concentrations related to CYP2D6 inactivity, especially due to increased HTF concentrations.


Subject(s)
Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP3A/genetics , Tamoxifen/analogs & derivatives , Tamoxifen/blood , Adult , Aged , Aged, 80 and over , Enzyme Activation/physiology , Female , Humans , Male , Middle Aged
10.
Oncol Rep ; 33(1): 439-47, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25338647

ABSTRACT

Estrogens and tamoxifen do not only exert their effects at the genomic level, but also play a role at the cell membrane activating downstream signaling pathways. We recently characterized an estrogen receptor-positive epithelial murine breast cancer cell line, LM05-E. Utilizing this cell line and MCF-7 cells, we compared the non-genomic effects of estradiol and 4-OH-tamoxifen. We showed that, similar to estradiol, tamoxifen activated the MAPK/ERK 1/2 pathway; however, we did not find activation of PI3K/AKT by either estradiol or tamoxifen. Short-term treatments with estradiol stimulated, whereas tamoxifen inhibited cell proliferation. Using pharmacological inhibitors we showed that the effect of estradiol was mediated by the MAPK/ERK 1/2 pathway, but that inhibition of this pathway did not affect tamoxifen. Surprisingly, however, blocking of PI3K/AKT signaling interfered with the inhibitory effect of tamoxifen. Analysis of the involvement of the EGFR support previous findings that designate this receptor as a mediator of the non-genomic effects of estradiol; blocking EGFR also reverses the inhibitory effect of tamoxifen. Finally, matrix metalloproteinases (MMPs) were confirmed to be involved in the proliferative effect of estradiol. These results demonstrated the novel non-genomic effects of tamoxifen and revealed that pathways downstream of EGFR and PI3K/AKT are involved in the inhibition of cell proliferation. Caution should be exercised when analyzing strategies that aim at combining endocrine therapy with specific signaling inhibitors.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estradiol/pharmacology , Tamoxifen/analogs & derivatives , Animals , Breast Neoplasms/pathology , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , MCF-7 Cells/drug effects , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Quinazolines/pharmacology , Signal Transduction/drug effects , Tamoxifen/pharmacology , Tyrphostins/pharmacology
11.
Menopause ; 22(7): 786-96, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25423325

ABSTRACT

OBJECTIVE: Treatment of menopausal symptoms by compounds with tissue-selective estrogen agonist/antagonist effects, often called selective estrogen receptor modulators, has been researched as an alternative to the use of estrogen therapy. These structurally diverse molecules elicit tissue-dependent responses in hormone-responsive tissues and organs, exhibiting variations in estrogenic activity in preclinical models of postmenopausal reproductive tissues that may improve postmenopausal women's health (eg, prevention and treatment of breast cancer, osteoporosis, and vulvar and vaginal atrophy). METHODS: This literature review investigates whether preclinical data predicted the clinical effects of ospemifene on female reproductive and urinary tract tissues and compares these findings with the specific vaginal effects of other estrogen receptor agonists/antagonists (tamoxifen, raloxifene, and bazedoxifene) in preclinical and clinical studies. Lasofoxifene, although not currently available, is included because of its unique effects on vaginal tissue. RESULTS: The response of endometrial and vaginal tissues to estrogen receptor agonists/antagonists can be differentiated using transvaginal ultrasound, endometrial histopathology, cytologic examination of vaginal smears, assessment of physical changes in the vagina, and relief of symptoms associated with vulvar and vaginal atrophy (such as dyspareunia). CONCLUSIONS: Available evidence indicates that ospemifene has unique effects on tissue, leading to a favorable long-term profile for the relief of vulvar and vaginal atrophy compared with other estrogen receptor agonists/antagonists (eg, tamoxifen, raloxifene, and bazedoxifene) with no short-term concerns about endometrial safety (based on endometrial hyperplasia, carcinoma, endometrial spotting, and endometrial bleeding).


Subject(s)
Estrogen Antagonists/pharmacology , Menopause/drug effects , Tamoxifen/analogs & derivatives , Translational Research, Biomedical , Urogenital System/drug effects , Female , Female Urogenital Diseases/drug therapy , Humans , Tamoxifen/pharmacology
12.
Climacteric ; 18(2): 226-32, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25252699

ABSTRACT

BACKGROUND: Ospemifene is a non-estrogen, tissue selective estrogen receptor agonist/antagonist, or selective estrogen receptor modulator, recently approved for the treatment of dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause. Postmenopausal dyspareunia is often associated with female sexual dysfunction (FSD). In this report, we present data that demonstrate the effect of ospemifene 60 mg/day on FSD assessed by the Female Sexual Function Index (FSFI), a widely used tool with six domains (Arousal, Desire, Orgasm, Lubrication, Satisfaction, and Pain). METHODS: A phase-3, randomized, double-blind, 12-week trial (n = 919) compared the efficacy and safety of oral ospemifene 60 mg/day vs. placebo in postmenopausal women with VVA in two strata based on self-reported, most bothersome symptom of either dyspareunia or dryness. Primary data were published previously. We report herein pre-specified secondary efficacy endpoints analyses, including changes from baseline to Weeks 4 and 12 for FSFI total and domain scores as well as serum hormone levels. RESULTS: Ospemifene 60 mg/day demonstrated a significantly greater FSFI total score improvement vs. placebo at Week 4 (p < 0.001). Improvement in FSFI scores continued to Week 12 (p < 0.001). At Week 4, the FSFI domains of Sexual Pain, Arousal, and Desire were significantly improved with ospemifene vs. placebo; at Week 12, improvements in all domains were significant (p < 0.05). Changes in serum hormones were minor and uncorrelated with changes in sexual functioning. CONCLUSION: In a large, randomized, double-blind, placebo-controlled trial, ospemifene 60 mg/day significantly improved FSD in women with VVA. Consistent effects across FSFI domains were observed.


Subject(s)
Selective Estrogen Receptor Modulators , Sexual Dysfunction, Physiological/drug therapy , Tamoxifen/analogs & derivatives , Vagina/pathology , Vulva/pathology , Aged , Atrophy , Double-Blind Method , Dyspareunia/drug therapy , Female , Hormones/blood , Humans , Middle Aged , Placebos , Sexual Dysfunction, Physiological/etiology , Surveys and Questionnaires , Tamoxifen/therapeutic use , Treatment Outcome
13.
Breast Cancer Res Treat ; 148(3): 571-80, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25395315

ABSTRACT

Ethnic differences in patient genetics and breast cancer (BC) biology contribute to ethnic disparities in cancer presentation and patient outcome. We prospectively evaluated SNPs within phase I and phase II tamoxifen (TAM) metabolizing enzymes, and the estrogen receptor gene (ESR1), aiming to identify potential pharmacogenomic ethnicity patterns in an ER-positive BC cohort constituted of Hispanic and Non-Hispanic White (NHW) women in South Texas. Plasma concentrations of TAM/metabolites were measured using HPLC. CYP2C9, CYP2D6 and SULT1A1 genotypes were determined by DNA sequencing/Pyrosequencing technology. ESR1 PvuII and XbaI SNPs were genotyped using Applied Biosystems Taqman Allelic Discrimination Assay. Hispanics had higher levels of TAM, 4-hydroxytamoxifen, and endoxifen than NHWs. There was a higher prevalence of CYP2D6 EM within Hispanics than NHWs, which corresponded to higher endoxifen levels, but no differences were verified with regard to CYP2C9 and SULT1A1. We found a higher incidence of the wild type forms of the ESR1 in Hispanics than NHWs. The performance status, the disease stage at diagnosis, and the use of aromatase inhibitors might have overcome the overall favorable pharmacogenomics profile of Hispanics when compared to NHWs in relation to TAM therapy responsiveness. Our data strongly point to ethnical peculiarities related to pharmacogenomics and demographic features of TAM treated Hispanics and NHWs. In the era of pharmacogenomics and its ultimate goal of individualized, efficacious and safe therapy, cancer studies focused on the Hispanic population are warranted because this is the fastest growing major demographic group, and an understudied segment in the U.S.


Subject(s)
Breast Neoplasms/drug therapy , Estrogen Receptor alpha/genetics , Pharmacogenetics , Tamoxifen/administration & dosage , Aged , Alleles , Arylsulfotransferase/genetics , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2D6/genetics , Female , Genotype , Hispanic or Latino , Humans , Middle Aged , Polymorphism, Single Nucleotide , Tamoxifen/adverse effects , Tamoxifen/analogs & derivatives , Tamoxifen/metabolism
14.
Nursing ; 44(2): 44-54; quiz 54-6, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24430389

Subject(s)
Anticoagulants , Antidiarrheals , Antitubercular Agents , Drug Approval , Hypoglycemic Agents , Abatacept/analysis , Abatacept/pharmacology , Abatacept/therapeutic use , Adult , Anticoagulants/analysis , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Antidiarrheals/analysis , Antidiarrheals/pharmacology , Antidiarrheals/therapeutic use , Antitubercular Agents/analysis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Benzazepines/analysis , Benzazepines/pharmacology , Benzazepines/therapeutic use , Canagliflozin/analysis , Canagliflozin/pharmacology , Canagliflozin/therapeutic use , Dimethyl Fumarate/analysis , Dimethyl Fumarate/pharmacology , Dimethyl Fumarate/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/analysis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dyspareunia/drug therapy , Humans , Hypoglycemic Agents/analysis , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Multiple Sclerosis/drug therapy , Obesity/drug therapy , Oligonucleotides/analysis , Oligonucleotides/pharmacology , Oligonucleotides/therapeutic use , Piperidines/analysis , Piperidines/pharmacology , Piperidines/therapeutic use , Proanthocyanidins/analysis , Proanthocyanidins/pharmacology , Proanthocyanidins/therapeutic use , Tamoxifen/analogs & derivatives , Tamoxifen/analysis , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , Uracil/analogs & derivatives , Uracil/analysis , Uracil/pharmacology , Uracil/therapeutic use
15.
J Pharm Biomed Anal ; 76: 13-20, 2013 Mar 25.
Article in English | MEDLINE | ID: mdl-23291438

ABSTRACT

A highly sensitive HPLC-UV method for the simultaneous determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in human plasma samples was developed and validated. The method employs a two step liquid-liquid extraction and a reversed phase separation on a Hypersil Gold(®) C18 column (150mm×4.6mm, 5µm) with isocratic elution. Mobile phase was a mixture of triethylammonium phosphate buffer 5mM pH 3.3 and acetonitrile (57:43, v/v). Total analytical run time was 16min. Precision assays showed CV % lower than 10.53% and accuracy in the range of 93.0-104.2%. The lower limits of quantification (0.75-8.5ngml(-1)) are adequate to measure clinically relevant concentrations in plasma samples. The method was successfully applied to 110 clinical plasma samples. Median plasma levels and interquartile range were: tamoxifen 55.77ngml(-1) (38.42-83.69ngml(-1)), N-desmethyltamoxifen 124.83ngml(-1) (86.81-204.80ngml(-1)), 4-hydroxytamoxifen 1.09ngml(-1) (0.76-1.53ngml(-1)) and endoxifen 6.18ngml(-1) (4.17-8.22ngml(-1)). The procedure has adequate analytical performance and can be employed in therapeutic drug monitoring of tamoxifen or pharmacokinetics studies.


Subject(s)
Antineoplastic Agents, Hormonal/blood , Chromatography, High Pressure Liquid/methods , Tamoxifen/blood , Antineoplastic Agents, Hormonal/metabolism , Drug Monitoring/methods , Female , Humans , Limit of Detection , Sensitivity and Specificity , Tamoxifen/analogs & derivatives , Tamoxifen/metabolism
16.
Ther Drug Monit ; 34(4): 422-31, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22777153

ABSTRACT

BACKGROUND: An association between CYP2D6 variation and clinical outcomes among women with breast cancer treated with tamoxifen (TAM) has been demonstrated, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes. This association is mainly due to the CYP2D6-mediated hydroxylation of N-desmethyltamoxifen (NDT) to yield endoxifen (EDF), which because of its high antiestrogenic potency, is mainly responsible for the therapeutic efficacy of TAM. The aim of this study was to evaluate the relation of CYP2D6 genotyping and phenotyping with EDF levels and [NDT]/[EDF] metabolic ratio in breast cancer patients from South of Brazil under TAM therapy. METHODS: Trough blood samples were collected from 97 patients. CYP2D6 genotyping was performed with a luminex assay and calculation of genotypic activity scores. Tamoxifen and metabolites EDF, NDT, and 4-hydroxy-TAM were measured in plasma by high performance liquid chromatography with photo diode array detector. CYP2D6 phenotyping was performed by the determination of dextromethorphan (DMT) and dextrorphan (DTF) by high-performance liquid chromatography with fluorescence detection at plasma collected 3 hours after oral administration of 33 mg of DMF. Phenotypes were given according to [DMT]/[DTF] metabolic ratio. RESULTS: CYP2D6 genotyping indicated a prevalence of 4.1% poor metabolizer, 4.1% intermediate metabolizer, 49.5% extensive metabolizer slow activity, 39.2% extensive metabolizer fast activity, and 3.1% ultrarapid metabolizer. Genotype (genotypic activity scores) was significantly correlated with phenotype ([DMT]/[DTF]), with a moderate association (rs = -0.463; P < 0.001). Median plasma concentrations (nanograms per milliliter; N = 97) were TAM 57.17; 4-hydroxy-TAM 1.01; EDF 6.21; NDT 125.50. EDF levels were lower in poor metabolizers than that in extensive metabolizers (P < 0.05). Phenotype showed stronger, but still moderate, association with EDF and [NDT]/[EDF] than genotype (r = -0.507, r = 0.625, P < 0.001 versus r = 0.356, r = 0.516, P < 0.01). Phenotype accounted for 26% of the variability in EDF levels and 38% of [NDT]/[EDF], whereas genotype accounted for 12% and 27%, respectively. CONCLUSIONS: CYP2D6 genotyping and/or phenotyping could not fully predict EDF concentrations. Monitoring EDF itself could be considered during TAM therapy.


Subject(s)
Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacokinetics , Tamoxifen/therapeutic use , Adult , Aged, 80 and over , Brazil , Breast Neoplasms/genetics , Cytochrome P-450 CYP2D6 Inhibitors , Dextromethorphan/blood , Dextrorphan/blood , Female , Genotype , Humans , Hydroxylation , Middle Aged , Phenotype , Tamoxifen/blood
17.
J Cardiovasc Pharmacol ; 58(6): 647-53, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21885992

ABSTRACT

The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher Emax than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; Emax = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Aorta, Thoracic/drug effects , Tamoxifen/pharmacology , Vasodilation/drug effects , Animals , Antineoplastic Agents, Hormonal/metabolism , Aorta, Thoracic/metabolism , Estradiol/analogs & derivatives , Estradiol/pharmacology , Fulvestrant , Indomethacin/pharmacology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Prostaglandins/biosynthesis , Rats , Rats, Wistar , Tamoxifen/analogs & derivatives , Tamoxifen/metabolism
18.
Basic Clin Pharmacol Toxicol ; 104(5): 400-7, 2009 May.
Article in English | MEDLINE | ID: mdl-19413660

ABSTRACT

Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD(2) = 2.2 +/- 0.06 and 1.9 +/- 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD(2) = 2.5 +/- 0.04 after N-desmethyl-tamoxifen, 2.5 +/- 0.03 after 4-hydroxy-tamoxifen, and 2.6 +/- 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.


Subject(s)
Endothelium, Vascular/drug effects , Tamoxifen/analogs & derivatives , Vascular Resistance/drug effects , Animals , Blood Pressure/drug effects , Endothelium, Vascular/metabolism , Heart Rate/drug effects , Male , Nitric Oxide/blood , Oxidative Stress/drug effects , Perfusion , Rats , Rats, Wistar , Tamoxifen/metabolism , Tamoxifen/pharmacology , Thiobarbituric Acid Reactive Substances/analysis
19.
Steroids ; 71(6): 417-28, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16481019

ABSTRACT

The estrogen receptor, ER, is an important biological target whose inhibition is known to be therapeutically relevant in the treatment of postmenopausal osteoporosis. In the present study, two prediction methods (CoMFA and GRIND (Almond)) were used to describe the binding modes of a set of estrogen receptor ligands. The critical alignment step presented in CoMFA was solved by using the information of the molecular descriptors space generated by grid-independent descriptors (GRIND). Then, it was possible to build robust and high predictive models based on the alignment-independent model. Since the structure of estrogen receptor is solved, the results of the present 3D QSAR models, given by the PLS maps based on molecular interaction fields (MIF) were compared to ligand-binding ER domains and showed good agreement.


Subject(s)
Quantitative Structure-Activity Relationship , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/metabolism , Binding Sites , Binding, Competitive , Breast Neoplasms/pathology , Cell Line, Tumor , Computer Simulation , Estrogens/chemistry , Estrogens/metabolism , Female , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Ligands , Models, Molecular , Molecular Conformation , Molecular Structure , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/metabolism , Reproducibility of Results , Tamoxifen/analogs & derivatives , Tamoxifen/chemistry , Tamoxifen/metabolism
20.
Biochem Cell Biol ; 82(2): 335-42, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15060629

ABSTRACT

Estrogen receptor (ER)-negative breast carcinomas are often difficult to treat with antiestrogens. This work was performed to determine if the re-expression of the human ER alpha could restore the hormone response of these cells. We have transfected the human wild-type ER alpha to an ER-negative breast cancer cell line (MDA-MB-231) using a tetracycline-regulated gene expression system. We obtained a new cell line, MDA-A4-5/2. Cell count and flow cytometry "S" phase cell fraction showed that 17-beta-estradiol induced an inhibition on the proliferation of these cells; on the contrary, the antiestrogens ICI 182 780, and tamoxifen blocked this effect. Finally, we demonstrated an induction of the endogenous progesterone receptor gene when ER alpha was present. These results suggest that the re-expression of ER alpha in ER-negative breast cancer cells recreate, at least partially, a hormone-responsive phenotype and may be useful as a therapeutic approach to control this pathology.


Subject(s)
Breast Neoplasms/metabolism , Estradiol/analogs & derivatives , Estrogen Receptor alpha/physiology , Estrogens/physiology , Tamoxifen/analogs & derivatives , Breast Neoplasms/pathology , Cell Division/drug effects , Cell Division/physiology , Cell Line, Tumor , Chloramphenicol O-Acetyltransferase/genetics , Clone Cells , Doxycycline/pharmacology , Estradiol/metabolism , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Estrogen Receptor alpha/biosynthesis , Estrogen Receptor alpha/genetics , Flow Cytometry , Fulvestrant , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/physiology , Humans , Luciferases , Receptors, Progesterone/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , S Phase/drug effects , Tamoxifen/pharmacology , Transfection
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