Bioactivation of clozapine by murine cardiac tissue in vivo and in vitro
| Autor: | Munir Pirmohamed, James L. Maggs, J. Steven Leeder, Charles John O'donnell, Dominic P. Williams, Jack Uetrecht, B. Kevin Park |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Liver cytology Metabolite Cardiomyopathy Pharmacology Toxicology Mass Spectrometry Pathogenesis chemistry.chemical_compound Mice In vivo Microsomes medicine Animals Clozapine Biotransformation Dose-Response Relationship Drug Molecular Structure Myocardium Proteins General Medicine Glutathione medicine.disease chemistry Liver Microsome medicine.drug Chromatography Liquid |
| Zdroj: | Chemical research in toxicology. 16(10) |
| ISSN: | 0893-228X |
| Popis: | Clozapine, an atypical neuroleptic, undergoes bioactivation to a chemically reactive nitrenium ion. This has been implicated in the pathogenesis of clozapine-induced agranulocytosis. Clozapine also causes myocarditis and cardiomyopathy, the mechanisms of which are unknown. To investigate this, we have evaluated whether clozapine undergoes bioactivation by murine cardiac tissue, in comparison to hepatic tissue. Mice were administered clozapine (5 and 50 mg/kg i.p.), and the extent of covalent binding was assessed by Western blotting. There was an increase in irreversible binding of clozapine to several proteins, ranging in mass from 30 to 250 kDa in both hepatic and cardiac tissue. Bioactivation by hepatic and cardiac microsomes was assessed by LC/MS using glutathione to trap the intermediate. Metabolism of radiolabeled clozapine to a glutathionyl conjugate by liver and cardiac microsomes was 30.5 +/- 3.3 and 3.6 +/- 0.3% of the initial incubation concentration, respectively. Ketoconazole (20 muM), a P450 inhibitor, significantly reduced binding in both hepatic and cardiac microsomes to 6.2 +/- 0.2 and 0.5 +/- 0.06%, respectively. These data indicate that clozapine undergoes bioactivation in the heart to a chemically reactive nitrenium metabolite that may be important in the pathogenesis of myocarditis and cardiomyopathy observed in man. |
| Databáze: | OpenAIRE |
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