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Alpha-1-acid glycoprotein imatinib

Meinolf Suttorp, Martin Bornhäuser, Markus Metzler, Frédéric Millot, Eberhard Schleyer
The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment...
October 27, 2017: Expert Review of Clinical Pharmacology
Sander Bins, Karel Eechoute, Jacqueline S L Kloth, Femke M de Man, Astrid W Oosten, Peter de Bruijn, Stefan Sleijfer, Ron H J Mathijssen
BACKGROUND: For imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the main cause of the lowering in imatinib exposure over time. METHODS: We prospectively measured imatinib trough concentration (Cmin ) values in 28 patients with gastrointestinal stromal tumours, at 1, 3 and 12 months after the start of imatinib treatment...
March 2017: Clinical Pharmacokinetics
Nader I Al-Dewik, Andrew P Jewell, Mohammed A Yassin, Hisham M Morsi
Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment...
2015: Biomarkers in Cancer
Svenja Beckmann, Thavy Long, Christina Scheld, Rudolf Geyer, Conor R Caffrey, Christoph G Grevelding
In the search for new drugs and drug targets to treat the flatworm disease schistosomiasis, protein kinases (PKs) have come under particular scrutiny because of their essential roles in developmental and physiological processes in schistosome parasites. In this context the application of the anti-cancer Abl tyrosine kinase (TK) inhibitor Imatinib (Gleevec/Glivec; STI-571) to adult Schistosoma mansoni in vitro has indicated negative effects on diverse physiological processes including survival. Motivated by these in vitro findings, we performed in vivo experiments in rodent models of S...
December 2014: International Journal for Parasitology, Drugs and Drug Resistance
Zdenek Racil, Filip Razga, Hana Klamova, Jaroslava Voglova, Petra Belohlavkova, Ludmila Malaskova, David Potesil, Jan Muzik, Daniela Zackova, Katerina Machova Polakova, Zbynek Zdrahal, Jana Malakova, Jiri Suttnar, Jan Dyr, Jiri Mayer
This multicentre study focused on monitoring imatinib mesylate (IMA) trough plasma (Ctrough ) and intracellular (IMA Cintrac ) concentrations in 228 chronic myelogenous leukaemia patients. The median of measured IMA Ctrough in our patient group was 905.8 ng ml (range: 27.7-4628.1 ng/ml). We found a correlation between IMA Ctrough and alpha 1-acid glycoprotein plasma concentrations (rS = 0.42; p < 0.001). All other analysed parameters revealed only weak (gender, dose of IMA per kg) or not significant (age, albumin, creatinine plasma concentration or body mass index) impact on measured IMA Ctrough...
June 2014: Hematological Oncology
Peggy Gandia, Cécile Arellano, Thierry Lafont, Françoise Huguet, Laurence Malard, Etienne Chatelut
PURPOSE: The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations...
February 2013: Cancer Chemotherapy and Pharmacology
Gian Wan Soo, Jason H K Law, Elaine Kan, Shin Yee Tan, Wei Yin Lim, Grace Chay, Nadeem I Bukhari, Ignacio Segarra
Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution...
August 2010: Anti-cancer Drugs
Ying Chen, Sagar Agarwal, Naveed M Shaik, Cliff Chen, Zheng Yang, William F Elmquist
The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP...
September 2009: Journal of Pharmacology and Experimental Therapeutics
Lin Zhou, Kari Schmidt, Frederick R Nelson, Veronica Zelesky, Matthew D Troutman, Bo Feng
The role of breast cancer resistance protein (Bcrp) and the combined activities of Bcrp and P-glycoprotein (P-gp, Mdr1a/1b) in limiting the brain penetration of drugs at the blood-brain barrier (BBB) were investigated using wild-type FVB, Mdr1a/1b(-/-), (-/-), Bcrp(-/-), and Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice. Four drugs, flavopiridol, imatinib mesylate (Gleevec), PF-407288, and prazosin, with different transport specificity for BCRP/Bcrp and MDR1/Mdr1a were selected, and the drug levels in plasma, cerebrospinal fluid, and brain of mice were determined...
May 2009: Drug Metabolism and Disposition: the Biological Fate of Chemicals
N Widmer, L A Decosterd, S Leyvraz, M A Duchosal, A Rosselet, M Debiec-Rychter, C Csajka, J Biollaz, T Buclin
Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis...
May 20, 2008: British Journal of Cancer
Joseph Gibbons, Merrill J Egorin, Ramesh K Ramanathan, Pingfu Fu, Daniel L Mulkerin, Stephen Shibata, Chris H M Takimoto, Sridhar Mani, Patricia A LoRusso, Jean L Grem, Anna Pavlick, Heinz-Josef Lenz, Susan M Flick, Sherrie Reynolds, Theodore F Lagattuta, Robert A Parise, Yanfeng Wang, Anthony J Murgo, S Percy Ivy, Scot C Remick
PURPOSE: This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients. PATIENTS AND METHODS: Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg...
February 1, 2008: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Momoyo Azuma, Yasuhiko Nishioka, Yoshinori Aono, Mami Inayama, Hideki Makino, Jun Kishi, Masayuki Shono, Katsuhiro Kinoshita, Hisanori Uehara, Fumitaka Ogushi, Keisuke Izumi, Saburo Sone
RATIONALE: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect. OBJECTIVES: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance. METHODS: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing...
December 15, 2007: American Journal of Respiratory and Critical Care Medicine
Catherine Delbaldo
Imatinib (Glivec) is a specific inhibitor of tyrosine kinase receptor, in particular of the proto-oncogene c-kit. Proto-oncogene c-kit is expressed or mutated in stromal digestive tumors (GIST). Pharmacokinetic (PK) analysis showed that imatinib displayed linear PK in patients with advanced GIST. Imatinib is extensively metabolized by the cytochrome P450 enzyme system. Alpha-1-acid glycoprotein (AAG), a protein involved in the acute phase of inflammation, is implicated in protein binding of imatinib and seems to play a key role in imatinib PK...
March 2007: Thérapie
N Widmer, L A Decosterd, C Csajka, S Leyvraz, M A Duchosal, A Rosselet, B Rochat, C B Eap, H Henry, J Biollaz, T Buclin
AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined...
July 2006: British Journal of Clinical Pharmacology
Olivier Kretz, H Markus Weiss, Martin M Schumacher, Gerhard Gross
AIMS: To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species. METHODS: The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds. RESULTS: The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%)...
August 2004: British Journal of Clinical Pharmacology
Angela Brieger, Simone Boehrer, Simone Schaaf, Daniel Nowak, Martin Ruthardt, Soo-Zin Kim, Peter Atadja, Dieter Hoelzer, Paris S Mitrou, Eckhart Weidmann, Kai Uwe Chow
In a variety of malignant cells the prostate-apoptosis-response-gene-4 (Par-4) induces increased sensitivity towards chemotherapeutic agents by down-regulating anti-apoptotic B-cell lymphoma-gene 2 (Bcl-2). Hypothesizing that Par-4 also influences apoptosis in myeloid cell lines, we tested this hypothesis by stably transfecting bcr-abl transformed-K562 cells with a Par-4-expressing vector. Here we demonstrate that over-expression of Par-4 in K562 cells up-regulates expression levels of Bcl-2 and death-associated protein (Daxx)...
July 1, 2004: Biochemical Pharmacology
Jérôme Larghero, Thibaut Leguay, Samia Mourah, Isabelle Madelaine-Chambrin, Anne Laure Taksin, Emmanuel Raffoux, Jean Noel Bastie, Laurent Degos, Patrice Berthaud, Jean Pierre Marolleau, Fabien Calvo, Christine Chomienne, François Xavier Mahon, Philippe Rousselot
The Abl tyrosine kinase inhibitor imatinb is becoming a standard for the treatment of chronic myelogenous leukemia (CML). However, Bcr-Abl gene mutations have been reported mainly in relapsing or resistant patients. In primary resistant patients, only few mutations have been documented so far, suggesting alternative mechanisms. We aimed to investigate if alpha 1 acid glycoprotein (AGP), an acute phase drug binding protein, could be a biological marker for pharmacological resistance to imatinib in nine patients in acute phase CML...
November 15, 2003: Biochemical Pharmacology
Philipp Le Coutre, Karl-Anton Kreuzer, Il-Kang Na, Michaela Schwarz, Joachim Lupberger, Matthias Holdhoff, Gökben Baskaynak, Harald Gschaidmeier, Uwe Platzbecker, Gerhard Ehninger, Witold Prejzner, Dieter Huhn, Christian A Schmidt
Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR...
August 2003: American Journal of Hematology
Kanako Uno, Takeshi Inukai, Nobuhiko Kayagaki, Kumiko Goi, Hiroki Sato, Atsushi Nemoto, Kazuya Takahashi, Keiko Kagami, Noriko Yamaguchi, Hideo Yagita, Ko Okumura, Toshiko Koyama-Okazaki, Toshio Suzuki, Kanji Sugita, Shinpei Nakazawa
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines...
May 1, 2003: Blood
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