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: Available online 22 July 2018Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(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, B and 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. Revie...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research

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ConclusionWhen performed adequately, CNB is a good substitute to SEB. Strict and specific guidelines need to be updated and adopted to direct on how and when it can be used, including the recommendation of concomitant complementary diagnostic laboratory testing such as flow cytometry. The latter should be readily available in order not to compromise the quality and the accuracy of the rendered diagnoses.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
The objective of this analysis was to describe the association between white blood cell (WBC) levels and occurrence of thrombotic events among patients with PV from a large real-world population.Patients and MethodsThis retrospective analysis using Veterans Health Administration claims data (October 1, 2005, to September 30, 2012) evaluated adult patients assigned to 4 WBC categories (WBC
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: Available online 21 November 2019Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Mariana Koehler, Filipa Moita, José Cabeçadas, Maria Gomes da Silva
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
ConclusionOfficial titles are more informative than short titles on clinicaltrials.gov. However, both short and official titles often lack basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of format and content in study titles.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
This study aimed to determine the impact of treatment facility on overall survival outcomes in DLBCL patients stratified by IPI risk groups.MethodsThe National Cancer Database was utilized to identify patients diagnosed with DLBCL between 2004 and 2015. Patients were stratified by IPI risk score from low to high risk disease, and overall survival of those treated at academic centers were compared to those treated at non-academic centers.ResultsTreatment at academic centers was associated with a significantly improved overall survival for all DLBCL patients (108.3 months) when compared to non-academic centers (74.5 months, p
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: November 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 11Author(s):
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: November 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 11Author(s):
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: October 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 10Author(s):
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Publication date: October 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 10Author(s):
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
MorphoSys announced that their ongoing phase III B-MIND study of tafasitamab passed the interim analysis for futility in patients with relapsed or refractory diffuse large B-cell lymphoma.
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
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