Pharmacogenomics of Tamoxifen Therapy

2009 ◽  
Vol 55 (10) ◽  
pp. 1770-1782 ◽  
Author(s):  
Hiltrud Brauch ◽  
Thomas E Mürdter ◽  
Michel Eichelbaum ◽  
Matthias Schwab
Keyword(s):  
Cytochrome P450 ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Plasma Concentrations ◽  
Hot Flashes ◽  
Parent Drug ◽  
Endocrine Treatment ◽  
Active Metabolites ◽  
Recurrence Rates ◽  
Hormone Receptor Positive ◽  
Cyp2d6 Inhibitors

Abstract Background: Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor–positive breast cancer. Content: Tamoxifen requires enzymatic activation by cytochrome P450 (CYP) enzymes for the formation of active metabolites 4-hydroxytamoxifen and endoxifen. As compared with the parent drug, both metabolites have an approximately 100-fold greater affinity for the estrogen receptor and the ability to inhibit cell proliferation. The polymorphic CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence the plasma concentrations of active tamoxifen metabolites and the outcomes of tamoxifen-treated patients. In particular, nonfunctional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 alleles are associated with higher recurrence rates. Summary: Accordingly, CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) genotyping before treatment to predict metabolizer status may open new avenues for individualizing endocrine treatment, with the maximum benefit being expected for extensive metabolizers. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, which are used to treat hot flashes, should be avoided because they severely impair formation of the active metabolites.

scholarly journals Rifampin Greatly Reduces the Plasma Concentrations of Intravenous and Oral Oxycodone

2009 ◽  
Vol 110 (6) ◽  
pp. 1371-1378 ◽  
Author(s):  
Tuija H. Nieminen ◽  
Nora M. Hagelberg ◽  
Teijo I. Saari ◽  
Antti Pertovaara ◽  
Mikko Neuvonen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Cytochrome P450 3A ◽  
Time Curve ◽  
Cold Pain ◽  
Visual Analog Scales ◽  
Concentration Time ◽  
Heat Pain Threshold ◽  
Oxycodone Hydrochloride

Background Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. Methods The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Results Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. Conclusions Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

An Amperometric Cytochrome P450-2D6 Biosensor System for the Detection of the Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine and Fluvoxamine

2016 ◽  
Vol 44 ◽  
pp. 208-228 ◽  
Author(s):  
Rachel Fanelwa Ajayi ◽  
Ezo Nxusani ◽  
Samantha F. Douman ◽  
Anovuyo Jonnas ◽  
Priscilla Gloria Lorraine Baker ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Competitive Inhibition ◽  
Plasma Concentrations ◽  
Antidepressant Drug ◽  
Selective Serotonin ◽  
Cytochrome P450 2D6 ◽  
Biosensor System ◽  
P450 2D6

Paroxetine is the second most prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant drug, characterized by extensive inter-individual variation in steady state plasma concentrations resulting in drug toxicity amongst patinets. A nanopolymeric biosensor for studying the biotransformation of paroxetine is presented. The bioelectrode system consists of cytochrome P450-2D6 enzyme encapsulated in nanotubular poly (8-anilino-1-napthalene sulphonic acid) electrochemically deposited on gold. The biosensing procedure involved the determination of the extent of modulation of fluvoxamine responses to the P450-2D6 enzyme electrode after incubation in paroxetine standard solutions. Paroxetine inhibited the activity of cytochrome P450-2D6 (CYP2D6) resulting in a decrease in the fluvoxamine signal of the biosensor. The biosensor gave a linear analytical response for the paroxetine in the interval 0.005 and 0.05 μM, with a detection limit of 0.002 μM and a response time of 30 s. Electrochemical Michaelis–Menten kinetics of the reversible competitive inhibition of the fluvoxamine responses of the biosensor by 0, 0.05 and 0.1 μM paroxetine gave apparent Michaelis–Menten constant (KMapp) values of 1.00 μM, 1.11 μM and 1.25 μM, respectively. The corresponding value for the maximum response, IMAX was 0.02 A. The dissociation constant, KI, value evaluated from Dixon analysis of the paroxetine modulation data was estimated to be-0.02 μM while Cornish-Bowden analysis confirmed the competitive inhibitory characteristics of the enzyme.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 enzymes

1998 ◽  
Vol 12 (4_suppl) ◽  
pp. S89-S97 ◽  
Author(s):  
Sheldon H. Preskorn
Keyword(s):  
Cytochrome P450 ◽  
Plasma Levels ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Original Position ◽  
Selective Serotonin ◽  
Cytochrome P450 Enzymes ◽  
Extensive Body ◽  
Cyp 2D6

In 1993, it was first proposed that an important difference between selective serotonin reuptake inhibitors (SSRIs) was the degree of inhibition of the cytochrome P450 (CYP) enzyme 2D6 that they produced under usually dosing conditions (Preskorn, 1993). Specifically, fluoxetine and paroxetine, in contrast to sertraline, were identified as causing substantial increases in the plasma levels of coadministered drugs, which were principally dependent on CYP 2D6 for their metabolism. Over the next 5 years, this position was hotly contested (Preskorn and Nemeroff, 1997). However, an extensive body of research has now accumulated, which incontrovertibly supports the original position. This paper will reviews this research and extends the discussion to all five SSRIs and four other important CYP enzymes: 1A2, 2C9/10, 2C19, and 3A3/4.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Phase II Trial of Anastrozole Plus Goserelin in the Treatment of Hormone Receptor–Positive, Metastatic Carcinoma of the Breast in Premenopausal Women

2010 ◽  
Vol 28 (25) ◽  
pp. 3917-3921 ◽  
Author(s):  
Robert. W. Carlson ◽  
Richard Theriault ◽  
Christine M. Schurman ◽  
Edgardo Rivera ◽  
Cathie T. Chung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Antitumor Activity ◽  
Phase Ii ◽  
Hormone Receptor ◽  
Phase Ii Trial ◽  
Hot Flashes ◽  
Metastatic Breast ◽  
Premenopausal Women ◽  
Hormone Receptor Positive

Purpose To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor–positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin. Patients and Methods Premenopausal women with estrogen and/or progesterone receptor–positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity. Results Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities. Conclusion The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor–positive metastatic breast cancer.

scholarly journals Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

2011 ◽  
Vol 115 (6) ◽  
pp. 1251-1260 ◽  
Author(s):  
Sarah M. Brown ◽  
Michael Holtzman ◽  
Thomas Kim ◽  
Evan D. Kharasch
Keyword(s):  
Radioligand Binding ◽  
Competitive Inhibition ◽  
Antinociceptive Effect ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Biologically Active ◽  
Whole Body ◽  
Tail Flick ◽  
High Affinity

Background The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

Efavirenz-induced neurological symptoms in rare homozygote CYP2B6 *2/*2 (C64T)

2007 ◽  
Vol 18 (8) ◽  
pp. 575-576 ◽  
Author(s):  
Osamu Usami ◽  
Yugo Ashino ◽  
Yuichi Komaki ◽  
Masafumi Tomaki ◽  
Toshiya Irokawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cytochrome P450 ◽  
Plasma Concentrations ◽  
Highly Active ◽  
P450 Isozymes ◽  
Cytochrome P450 Isozymes ◽  
Hiv 1 ◽  
Rare Homozygote ◽  
Hepatic Cytochrome

Some of the HIV-1-infected patients who were given highly active anti-retroviral therapy (HAART) including efavirenz (EFV) presented adverse central nervous system (CNS) symptoms such as fatigue and insomnia. The incidence of adverse CNS symptoms is associated with hepatic cytochrome P450 isozymes (CYP2B6) polymorphisms. For example, CYP2B6 *6 (G516T and A785G) and *7 (G516T, A785G and C1459T) prolonged the EFV half-life despite discontinuation of EFV. CYP2B6 *2/*2 (C64T) is extremely rare and there have been no data describing the EFV plasma concentrations in C64T homozygous patients, who developed adverse CNS symptoms. C64T homozygous possibly has some catalytic defects.

Advances in Adjuvant Endocrine Therapy for Postmenopausal Women

2008 ◽  
Vol 26 (5) ◽  
pp. 798-805 ◽  
Author(s):  
Nancy U. Lin ◽  
Eric P. Winer
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Disease Free Survival ◽  
Breast Cancer Diagnosis ◽  
Endocrine Treatment ◽  
Future Research ◽  
Sequential Approach ◽  
Hormone Receptor Positive

Hormone receptor-positive cancers are the most common tumor subtype among postmenopausal women with breast cancer. Despite substantial improvements in disease-free survival and overall survival with tamoxifen and chemotherapy, recurrences still occur, and may ultimately lead to death from breast cancer. Importantly, disease recurrence includes both early and late events, with over half of all recurrences detected more than 5 years from initial breast cancer diagnosis. In recent years, a number of large, randomized trials have evaluated the role of the aromatase inhibitors (AIs) in postmenopausal women with hormone receptor-positive breast cancer. These studies have tested one of three approaches: (1) an upfront AI, (2) a sequential approach after 2-3 years of tamoxifen, and (3) extended endocrine therapy beyond 5 years. Results of these studies have challenged the previous standard of a 5-year course of tamoxifen alone. While the AIs have become a standard component of treatment for most postmenopausal women, many questions remain as to how best tailor endocrine treatment to individual patients. In addition, despite the gains achieved with the AIs, many recurrences are not prevented, and novel strategies are urgently needed, particularly for those women at high risk of recurrence. In this article, we review the efficacy and toxicity data from the available trials of endocrine therapy in the postmenopausal setting. We outline controversies in choosing the optimal endocrine approach, and we discuss selected ongoing studies. Finally, we highlight future research directions, such as the need to understand host and tumor heterogeneity.

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