clozapine has been researched along with pulegone* in 2 studies
2 other study(ies) available for clozapine and pulegone
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Profiling the reactive metabolites of xenobiotics using metabolomic technologies.
A predominant pathway of xenobiotic-induced toxicity is initiated by bioactivation. Characterizing reactive intermediates will provide information on the structure of reactive species, thereby defining a potential bioactivation mechanism. Because most reactive metabolites are not stable, it is difficult to detect them directly. Reactive metabolites can form adducts with trapping reagents, such as glutathione, which makes the reactive metabolites detectable. However, it is challenging to "fish" these adducts out from a complex biological matrix, especially for adducts generated via uncommon metabolic pathways. In this regard, we developed a novel approach based upon metabolomic technologies to screen trapped reactive metabolites. The bioactivation of pulegone, acetaminophen, and clozapine were reexamined by using this metabolomic approach. In all these cases, a large number of trapped reactive metabolites were readily identified. These data indicate that this metabolomic approach is an efficient tool to profile xenobiotic bioactivation. Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antipsychotic Agents; Clozapine; Cyclohexane Monoterpenes; Glutathione; Humans; Male; Metabolomics; Mice; Microsomes, Liver; Monoterpenes; Xenobiotics | 2011 |
A trapping method for semi-quantitative assessment of reactive metabolite formation using [35S]cysteine and [14C]cyanide.
A trapping approach for semi-quantitative assessment of bioactivation potential has been established for new chemical entities by using [(35)S]cysteine and [(14)C]sodium cyanide as trapping reagents. Reactive metabolites were trapped as radioactive adducts with the trapping reagents to be analyzed by radio-LC(/MS). As a reference, hepatotoxic drugs (clozapine, diclofenac, R-(+)-pulegone and troglitazone) were tested in the [(35)S]cysteine trapping assay and the proposed structures of the cysteine adducts were consistent with glutathione adducts previously reported. The accuracy of this methodology to predict bioactivation potential of structurally diverse non-radiolabeled test compounds was evaluated by comparing the radiochromatographic peak area obtained in this assays with the extent of covalent binding to protein assessed by the conventional method using radiolabeled test compounds. The value obtained from the [(35)S]cysteine trapping assay in human liver microsomes predicted potential for covalent binding of the test compounds to proteins with reasonable accuracy. A combination of trapping reagents ([(35)S]cysteine and [(14)C]cyanide) improved the accuracy for prediction of bioactivation potential by simultaneously trapping both types of electrophilic reactive metabolites. This method is expected to be a useful to prioritize compounds for further development based on the bioactivation liability, especially at the lead optimization stage. Topics: Biotransformation; Carbon Radioisotopes; Chromans; Clozapine; Cyclohexane Monoterpenes; Cysteine; Diclofenac; Humans; Microsomes, Liver; Monoterpenes; Pharmaceutical Preparations; Sodium Cyanide; Sulfur Radioisotopes; Technology, Pharmaceutical; Thiazolidinediones; Troglitazone | 2009 |