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Metabolism of N-methylformamide in mice: primary kinetic deuterium isotope effect and identification of S-(N-methylcarbamoyl)glutathione as a metabolite.
It is highly likely that N-methylformamide is oxidized and conjugated to form S-methylcarbamoyl)glutathione which is metabolized further to N-acetyl-S-(N-methyl CarbamoyL) cysteine, which could be hydrolyzed to give the parent thiol and the observed metabolic end products, methylamine and carbon dioxide. Expand
Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug.
The kinetics of DMXAA glucuronidation in vivo are likely to be linear and unaffected by the coadministration of most glucuronidated drugs, but plasmaDMXAA clearance may be decreased in patients with renal dysfunction, illustrating the utility of in vitro techniques for the prediction of potential drug interactions and other dispositional characteristics of newly developed anticancer drugs before their administration to patients. Expand
Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identifiedExpand
Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent
DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen, and Rapidly reversible dose-limiting toxicities were observed at 4900 mg m−2, including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Expand
Mechanisms of tumor vascular shutdown induced by 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA): Increased tumor vascular permeability
The hypothesis that DMXAA increases tumor vascular permeability both directly and through the induction of other vasoactive mediators, including TNF, might be useful clinically to potentiate theascular permeability of other anticancer modalities such as cytotoxic drugs, antibodies, drug conjugates and gene therapy. Expand
Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients
It is suggested that the interspecies differences in biological effects of thalidomide may be attributable, at least in part, to the differences in its metabolism and hence pharmacokinetics. Expand
Transport of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid and its acyl glucuronide by human intestinal Caco-2 cells.
Data indicate that the transport of DMXAA across Caco-2 monolayers was through a passive process, whereas the transportofDMXAA-G was mediated by MRP1/2. Expand
An investigation of the relationship between the hepatotoxicity and the metabolism of N-alkylformamides.
The hepatotoxicity and metabolism of the following close analogs of the hepatotoxic antitumor agent N-methylformamide (NMF) were investigated in CBA/CA mice and the results suggest that two metabolic pathways of N-alkylformamides can be distinguished. Expand
Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver.
It is demonstrated that DXAA undergoes extensive acyl glucuronidation followed by biliary excretion in the isolated perfused rat liver, and its hepatic metabolism may be saturable, and DXAA seems to be more extensively metabolized than FAA. Expand
The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice
The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour Necrosis factor can be replaced by other vasoactive factors in its antitumours action, an observation of relevance to current clinical studies. Expand