LC–MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation

Publication date: 25 October 2018Source: Journal of Pharmaceutical and Biomedical Analysis, Volume 160Author(s): Mohamed W. Attwa, Adnan A. Kadi, Haitham Alrabiah, Hany W. DarwishAbstractEntrectinib (RXDX-101) is orally available inhibitor of the tyrosine kinases including tropomyosin receptor kinases (Trk) A–C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK), with potential antineoplastic activity. Entrectinib (ENB) granted breakthrough designation by FDA for NTRK + Solid tumors. In vitro metabolism of ENB generates quinone methide and iminium reactive intermediates that were captured by potassium cyanide and GSH, respectively forming stable conjugates that were characterized by LC–MS/MS. Seven in vitro ENB metabolites were identified through four metabolic reactions including hydroxylation, N-dealkylation, N-oxidation and reduction. Furthermore, four reactive intermediates including two quinone methide and two iminium ions were detected and the bioactivation mechanisms were supposed. In vivo metabolism of ENB was done by giving single oral dose (35.2 mg/kg) to Sprague Dawley rats. In vivo metabolism generates five phase I metabolites similar to in vitro metabolism except no metabolic reactions were identified on indazole ring. One phase II metabolite was characterized in in vivo metabolism of ENB resulted from glucuronidation of hydroxyl metabolite of ENB. Reporting these data for ENB is very crucial in the development stage. Re...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research

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ConclusionsAn improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
Chem. Commun., 2019, Advance Article DOI: 10.1039/C9CC06603A, CommunicationCharmaine Hee, Diwei Ho, Amir Karton, Gareth Nealon, Jessica A. Kretzmann, Marck Norret, K. Swaminathan Iyer Polymers are an attractive anchoring platform for the synthesis of radioimmunoconjugates. To cite this article before page numbers are assigned, use the DOI form of citation above. The content of this RSS Feed (c) The Royal Society of Chemistry
Source: RSC - Chem. Commun. latest articles - Category: Chemistry Authors: Source Type: research
This study aimed to identify the clinicopathological characteristics and treatment associated with prognosis in patients with primary DLBCL of the breast. MATERIAL AND METHODS A retrospective study included the clinical and treatment data from 46 women with a histological diagnosis of primary DLBCL. Patients were staged using Ann Arbor staging criteria, overall survival (OS), progression-free survival (PFS), and the international prognostic index (IPI) scores were obtained. Laboratory finding included serum lactate dehydrogenase (LDH), and the immunohistochemistry findings were recorded. RESULTS Patients (n=46), included s...
Source: Medical Science Monitor - Category: Research Tags: Med Sci Monit Source Type: research
Within the last 2 years, the U.S. Food and Drug Administration approved 2 chimeric antigen receptor (CAR) T-cell therapies for relapsed/refractory diffuse large B-cell lymphoma, high-grade B cell lymphoma, and transformed follicular lymphoma ” axicabtagene ciloleucel or “axi-cel” (Yescarta, Kite Pharma) and tisagenlecleucel or “tisa-cel” (Kymriah, Novartis). Both products target CD19, a ubiquitous surface antigen on mature and malignant B-cells, but these chimeric receptors differ in their costimulatory domains (eg, CD28 for a xi-cel and 41-BB for tisa-cel), which affects pharmacokinetics, CAR...
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Tags: Clinical Investigation Source Type: research
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Source: International Journal of Clinical Oncology - Category: Cancer & Oncology Source Type: research
Source: ClinicoEconomics and Outcomes Research - Category: Health Management Tags: ClinicoEconomics and Outcomes Research Source Type: research
Blood Cancer Journal, Published online: 18 November 2019; doi:10.1038/s41408-019-0249-xMaternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma
Source: Blood Cancer Journal - Category: Hematology Authors: Source Type: research
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Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research
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Source: Nanomedicine: Nanotechnology, Biology and Medicine - Category: Nanotechnology Source Type: research
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Source: Blood Research - Category: Hematology Tags: Blood Res Source Type: research
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