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Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice
- Publication Year :
- 2013
-
Abstract
- Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram, thereby shifting BA production from blood to tissues. Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA, and metabolites were quantitated in plasma and urine, and toxicities were assessed. BEN had a plasma t½
- Subjects :
- Cancer Research
Metabolite
Aldehyde dehydrogenase
Antineoplastic Agents
Hematocrit
Pharmacology
Toxicology
Article
Excretion
chemistry.chemical_compound
Mice
Pharmacokinetics
White blood cell
Disulfiram
medicine
Animals
Pharmacology (medical)
Drug Interactions
Enzyme Inhibitors
biology
medicine.diagnostic_test
Chemistry
Aldehyde Dehydrogenase
medicine.anatomical_structure
Oncology
Area Under Curve
Benzaldehydes
Toxicity
biology.protein
Female
Chemical and Drug Induced Liver Injury
medicine.drug
Half-Life
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....d4940b0701df81a351f61aa8447b0716