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Belizatinib (BZB; TSR-011) is a next-generation anaplastic lymphoma kinase inhibitor that also inhibits tropomyosin-related kinases A/B/C. In this in-vitro study, we examined the formation of reactive metabolites from BZB using rat liver microsomes or human liver microsomes in the presence of a trapping agent (potassium cyanide) to generate iminium reactive intermediates. Identification of the in vitro BZB metabolites indicated that the major in-vitro metabolic reaction involved hydroxylation of the piperidine moiety. We identified eight in-vitro phase I metabolites and three iminium reactive intermediates, suggesting two possible BZB-bioactivation pathways. We propose that the tertiary nitrogen in the piperidine ring activates the attached benzyl carbon in addition to the two α carbons inside the ring. To our knowledge, this is the first report on the structural identification of reactive metabolites derived from BZB.
This article was published in the following journal.
Name: Journal of pharmaceutical and biomedical analysis
Kavain is an active and major component in Piper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing produ...
Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hept...
Many synthetic biology approaches aim at expanding the product diversity of enzymes or whole biosynthetic pathways. However, the chemical structure space of natural product forming routes is often res...
Pentachlorophenol (PCP) caused water quality problems owe to its past widespread application and stability, harmful to human health. Photocatalysis, which was mainly involved in the reactive oxygen sp...
Antibiotic contaminants have become a severe environmental problem in recent years and finding effective ways to deal with this issue is of great importance. In this study, Phanerochaete chrysosporium...
Dermal transfer efficiency has been defined as the amount of material that moves from one surface to another following contact. The investigators propose to measure dermal transfer effici...
Lung cancer is the most common cancer in men and the fourth most common cancer in women worldwide. Until today no effective method permits the early detection of lung cancer. Consequently,...
This study is designed to compare the effectiveness of reactive focal drug administration (RFDA) using dihydroartemisinin+piperaquine (DHAP) versus reactive focal test and treat (RFTAT) us...
The aim of this study is to assess the incidence and the clinical and therapeutic characteristics of reactive arthritis and to compare them with those of a historical cohort. We hypothesis...
Reactive or secondary thrombocytosis is defined as abnormally high platelet count (≥4,50,000 platelets per micro-liter) in the absence of chronic myeloproliferative disease. In criticall...
Nitrogenous products of NITRIC OXIDE synthases, ranging from NITRIC OXIDE to NITRATES. These reactive nitrogen intermediates also include the inorganic PEROXYNITROUS ACID and the organic S-NITROSOTHIOLS.
Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of signal transduction and gene expression, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.
The N-acetyl derivative of CYSTEINE. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates.
A group of related disorders characterized by LYMPHOCYTOSIS; HISTIOCYTOSIS; and hemophagocytosis. The two major forms are familial and reactive.
An aseptic, inflammatory arthritis developing secondary to a primary extra-articular infection, most typically of the GASTROINTESTINAL TRACT or UROGENITAL SYSTEM. The initiating trigger pathogens are usually SHIGELLA; SALMONELLA; YERSINIA; CAMPYLOBACTER; or CHLAMYDIA TRACHOMATIS. Reactive arthritis is strongly associated with HLA-B27 ANTIGEN.
Multiple Sclerosis MS
Multiple sclerosis (MS) is the most common disabling neurological condition affecting 100,000 young adults in the UK. The condition results from autoimmune damage to myelin, causing interference in nerve signaling. Symptoms experienced depend on the pa...