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imatinib metabolism

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https://www.readbyqxmd.com/read/29166334/gastrointestinal-stromal-tumor-of-the-prostate-staging-and-evaluation-of-response-to-therapy-with-18f-fdg-pet-ct
#1
Yazan Z Alabed
A 49-year-old man presented for routine general physical examination was found with an enlarged prostate gland without associated symptoms. Ultrasound followed by computed tomography (CT) of abdomen and pelvis confirmed a markedly enlarged heterogeneous prostate gland. Subsequently, a staging flourine-18 fluorodeoxyglucose (F-FDG) positron emission tomography (PET/CT) scan revealed intensely FDG-avid mass involving the prostate, which was biopsied as gastrointestinal stromal tumor (GIST). The patient was treated with imatinib and a follow-up PET/CT scan showed complete metabolic response...
November 22, 2017: Clinical Nuclear Medicine
https://www.readbyqxmd.com/read/29138287/clopidogrel-carboxylic-acid-glucuronidation-is-mediated-mainly-by-ugt2b7-ugt2b4-and-ugt2b17-implications-for-pharmacogenetics-and-drug-drug-interactions
#2
Helina Kahma, Anne M Filppula, Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Mikko T Holmberg, Matti K Itkonen, Moshe Finel, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29121435/altered-intracellular-signaling-by-imatinib-increases-the-anti-cancer-effects-of-tyrosine-kinase-inhibitors-in-cml-cells
#3
Takuya Hirao, Masashi Yamaguchi, Megumi Kikuya, Hiroji Chibana, Kousei Ito, Shigeki Aoki
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), improve the outcome of chronic myelogenous leukemia (CML) therapy. However, TKI treatment is long-term and can induce resistance to TKIs, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKIs...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29115640/off%C3%A2-target-effect-of-imatinib-and-nilotinib-on-human-vitamin-d3-metabolism
#4
Lysann Kroschwald, Meinolf Suttorp, Josephine Tabea Tauer, Nick Zimmermann, Claudia Günther, Andrea Bauer
Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL...
November 3, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28970330/early-response-evaluation-by-18-f-fdg-pet-influences-management-in-gastrointestinal-stromal-tumor-gist-patients-treated-with-imatinib-with-neo-adjuvant-intent
#5
Sheima Farag, Lioe-Fee de Geus-Oei, Winette T Van der Graaf, Frits van Coevorden, Dirk J Grunhagen, Anna K L Reyners, Pieter A Boonstra, Ingrid M E Desar, Hans J Gelderblom, Neeltje Steeghs
Objective: FDG-PET has previously proven to be an effective way for early response evaluation of imatinib treatment in GISTs. However, it is unclear whether this affects treatment decisions in GIST patients treated with neo-adjuvant intent. Methods: We retrospectively scored change in management based on the early response evaluation by FDG-PET scans in patients entered in the Dutch GIST registry and treated with neo-adjuvant imatinib . Results: Seventy FDG-PET scans in 63 patients treated with neo-adjuvant imatinib were conducted for early response evaluation...
September 28, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28920959/targeting-mitochondrial-oxidative-phosphorylation-eradicates-therapy-resistant-chronic-myeloid-leukemia-stem-cells
#6
Elodie M Kuntz, Pablo Baquero, Alison M Michie, Karen Dunn, Saverio Tardito, Tessa L Holyoake, G Vignir Helgason, Eyal Gottlieb
Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs...
October 2017: Nature Medicine
https://www.readbyqxmd.com/read/28900995/-association-between-genetic-polymorphisms-and-variation-of-imatinib-pharmacokinetics-in-gastrointestinal-stromal-tumors
#7
Haibo Qiu, Wei Zhuang, Xueding Wang, Min Huang, Zhiwei Zhou
OBJECTIVE: To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients. METHODS: Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS...
September 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28803208/n-glucuronidation-catalyzed-by-ugt1a4-and-ugt2b10-in-human-liver-microsomes-assay-optimization-and-substrate-identification
#8
Danyi Lu, Qian Xie, Baojian Wu
N-glucuronidation is an important pathway for metabolism and disposition of tertiary amines in humans. This reaction is mainly catalyzed by the enzymes UGT1A4 and UGT2B10. However, the metabolic patterns of UGT1A4- and UGT2B10-mediated N-glucuronidation are not fully clear. In this study, we first optimized in vitro reaction conditions for N-glucuronidation by using specific substrates (i.e., trifluoperazine for UGT1A4, cotinine and amitriptyline for UGT2B10). Furthermore, we found that hepatic N-glucuronidation showed significant species differences...
October 25, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28698448/-a-case-of-chronic-myelogenous-leukemia-that-developed-fibrous-pericarditis-owing-to-nilotinib-use
#9
Shogo Miura, Kazuyuki Murase, Akira Sakurada, Kohichi Takada, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Atsuko Muranaka, Kazutoshi Tachibana, Junji Kato
A 64-year-old man was diagnosed with chronic-phase chronic myelogenous leukemia(CML)in May 2009. He was treated with imatinib and achieved complete cytogenetic response(CCyR)in 2 months. After 4 months of treatment, he developed interstitial pneumonia and became intolerant to imatinib. He was then switched to nilotinib from October of the same year. In June 2013, he was diagnosed with drug-induced pericarditis resulting from nilotinib use, and thus, nilotinib was discontinued. Subsequently, he was followed up without specific treatment for CML...
June 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28690936/a-case-of-imatinib-induced-hepatitis
#10
Osman Bhatty, Mohammad Selim, Thamer Kassim, Lakshmi Chintalacheruvu, Manuel Urra, Sonia Shah, Joseph Haggerty, John Gross, Aravdeep Jhand, Gene Pershwitz, Jaya Gupta
A 71-year-old female with a past medical history of Philadelphia chromosome-positive chronic myelogenous leukemia on imatinib therapy, Sjogren's syndrome, and hypothyroidism presents with acute hepatitis. After a comprehensive workup ruling out viral, infectious and metabolic etiologies imatinib is stopped which results in immediate improvement. The biopsy is consistent with drug-induced liver damage; the patient is started on oral prednisone and discharged. Unfortunately, our patient's liver function does not improve over the course of the next week and she is readmitted for hepatic and renal failure...
June 1, 2017: Curēus
https://www.readbyqxmd.com/read/28659801/hepatocellular-toxicity-associated-with-tyrosine-kinase-inhibitors-mitochondrial-damage-and-inhibition-of-glycolysis
#11
Franziska Paech, Jamal Bouitbir, Stephan Krähenbühl
Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1-100 μM) for different periods of time and assessed toxicity...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28616912/-the-roles-of-glut5-in-imatinib-resistance-in-the-ph-acute-lymphoblastic-leukemia-cell
#12
Tian-You Yan, Duo-Lan Naren, Yu-Ping Gong
OBJECTIVES: To explore the possible roles of glucose transport 5 (Glut5) in imatinib resistance in the Ph(+) acute lymphoblastic leukemia cell (Ph(+) ALL). METHODS: The gene chip technique was used to detect different gene expression between Ph(+) ALL cell line SUP-B15/R (imatinib resistant cell line) and SUP-B15/S (imatinib sensitive cell line), the gene of solute carrier family 2 member 5 (SLC2A5) and its coded protein Glut5 were screened out and were reconfirmed by qPCR and Western blot assay...
May 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28557709/influence-of-cytochrome-p450-abc-and-slc-gene-polymorphisms-on-imatinib-therapy-outcome-of-patients-with-gastrointestinal-stromal-tumours-gist
#13
K Wasielewski, B Wasag, A Wozniak, J Pikiel, A Kowalik, C Osuch, E Bylina, J A Siedlecki, P Rutkowski, J Limon
The efficacy of imatinib-based therapy depends on the proteins involved in its metabolism and transportation. Therefore, the aim of our study was to investigate the possible correlation of selected P450, ABC and SLC polymorphic variants and the outcome of imatinib therapy. A total of 101 patients with advanced, KIT/PDGFRA(+) GIST treated with imatinib were enrolled to the study. DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP and direct sequencing. Deviation from the Hardy-Weinberg equilibrium was only observed for rs2740574...
2017: Folia Biologica (Praha)
https://www.readbyqxmd.com/read/28541695/discovery-of-potent-selective-stem-cell-factor-receptor-platelet-derived-growth-factor-receptor-alpha-c-kit-pdgfr%C3%AE-dual-inhibitor-for-the-treatment-of-imatinib-resistant-gastrointestinal-stromal-tumors-gists
#14
Yanli Lu, Fei Mao, Xiaokang Li, Xinyu Zheng, Manjiong Wang, Qing Xu, Jin Zhu, Jian Li
Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines...
June 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28445830/overexpression-of-heme-oxygenase-1-in-bone-marrow-stromal-cells-promotes-microenvironment-mediated-imatinib-resistance-in-chronic-myeloid-leukemia
#15
Ping Liu, Dan Ma, Zhengyu Yu, Nana Zhe, Mei Ren, Ping Wang, Meisheng Yu, Jun Huang, Qin Fang, Jishi Wang
Neoplasm cells from patients with chronic myeloid leukemia (CML) interact with stromal cells of the surrounding microenvironment. Bone marrow stromal cells (BMSCs) represent the main population in CML marrow stroma, which may play a key role in disease support and progression. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism that is associated with cell proliferation and resistance to apoptosis. We herein up-regulated HO-1 expression of BMSCs and evaluated whether BMSCs influenced K562 cells survival...
July 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28442505/overexpressed-fatty-acid-synthase-in-gastrointestinal-stromal-tumors-targeting-a-progression-associated-metabolic-driver-enhances-the-antitumor-effect-of-imatinib
#16
Chien-Feng Li, Fu-Min Fang, Yen-Yang Chen, Ting-Ting Liu, Ti-Chun Chan, Shih-Chen Yu, Li-Tzong Chen, Hsuan-Ying Huang
Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection...
August 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28433749/novel-sulphur-containing-imatinib-metabolites-found-by-untargeted-lc-hrms-analysis
#17
Ivo Vrobel, David Friedecký, Edgar Faber, Lukáš Najdekr, Kateřina Mičová, Radana Karlíková, Tomáš Adam
Untargeted metabolite profiling using high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS), followed by data analysis with the Compound Discoverer 2.0™ software, was used to study the metabolism of imatinib in humans with chronic myeloid leukemia. Plasma samples from control (drug-free) and patient (treated with imatinib) groups were analyzed in full-scan mode and the unknown ions occurring only in the patient group were then, as potential imatinib metabolites, subjected to multi-stage fragmentation in order to elucidate their structure...
June 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28411632/an-ultra-specific-and-sensitive-sandwich-elisa-for-imatinib-using-two-anti-imatinib-antibodies
#18
Tetsuya Saita, Yuta Yamamoto, Kazuhisa Hosoya, Yutaro Yamamoto, Sakiko Kimura, Yutaka Narisawa, Masashi Shin
The development of an immunoassay for a low-molecular-weight drug first requires the identification of specific antibodies that do not cross-react with the drug's metabolites. If two antibodies can simultaneously recognize the entire structure of the drug, we can then utilize them to establish an ultra-specific sandwich ELISA, free from interference due to the metabolic products of the drug. This paper reports an ultra-specific and sensitive sandwich ELISA for determination of the tyrosine kinase inhibitor imatinib using two anti-imatinib antibodies...
May 29, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28393622/the-importance-of-drug-metabolites-synthesis-the-case-study-of-cardiotoxic-anticancer-drugs
#19
Ivanna Hrynchak, Emília Sousa, Madalena Pinto, Vera Marisa Costa
Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far...
April 25, 2017: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/28385785/imatinib-and-spironolactone-suppress-hepcidin-expression
#20
Katarzyna Mleczko-Sanecka, Ana Rita da Silva, Debora Call, Joana Neves, Nikolai Schmeer, Georg Damm, Daniel Seehofer, Martina U Muckenthaler
Disorders of iron metabolism are largely attributed to an excessive or insufficient expression of hepcidin, the master regulator of systemic iron homeostasis. Here, we investigated whether drugs targeting genetic regulators of hepcidin can affect iron homeostasis. We focused our efforts on drugs approved for clinical use to enable repositioning strategies and/or to reveal iron-related side effects of widely prescribed therapeutics. To identify hepcidin-modulating therapeutics, we re-evaluated data generated by a genome-wide RNAi screen for hepcidin regulators...
July 2017: Haematologica
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