Journal ArticleDOI
In vitro evaluation of a toxic metabolite of sulfadiazine.
N H Shear,S P Spielberg +1 more
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TLDR
The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione, which could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.Abstract:
We have demonstrated the in vitro production of a potentially toxic metabolite of sulfadiazine Human lymphocytes were incubated with sulfadiazine and a murine hepatic microsomal drug metabolizing system. Toxicity to cells was assessed by trypan blue dye exclusion. Covalent binding of labelled sulfadiazine to microsomes also was studied. Sulfadiazine toxicity to cells was dependent on microsomes and NADPH. Binding and toxicity were decreased when microsomes were boiled or cytochrome P-450 inhibited, and by the addition of N-acetylcysteine or glutathione. The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione. Covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.read more
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Journal ArticleDOI
Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.
TL;DR: Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.
Journal ArticleDOI
Diagnosis of sulfonamide hypersensitivity reactions by in-vitro rechallenge with hydroxylamine metabolites
Michael J. Rieder,Jack Uetrecht,Neil H. Shear,Marilyn Cannon,Margaret A. Miller,Stephen P. Spielberg +5 more
TL;DR: Results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating hypersensitivity reactions to sulfonamide agents.
Journal ArticleDOI
Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions.
TL;DR: A slow acetylator phenotype is suggested to be a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.
Journal ArticleDOI
Drug disposition and drug hypersensitivity.
Journal ArticleDOI
The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions
TL;DR: It is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia.
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