Abstract
Differences in the incidence of adverse drug reactions to trimethoprim-sulfamethoxazole and dapsone may result from differences in the formation, disposition, toxicity, and/or detoxification of their hydroxylamine metabolites. In this study, we examine whether differences in the biochemical processing of sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) by erythrocytes [red blood cells (RBCs)] contribute to this differential incidence. The methemoglobin (MetHgb)-forming capacity of both metabolites was compared after a 60-min incubation with washed RBCs from four healthy human volunteers. DDS-NOH was significantly more potent (P = .004) but equally efficacious with SMX-NOH in its ability to form MetHgb. The elimination of potential differences in disposition by lysing RBCs did not change the MetHgb-forming potency of either hydroxylamine. At pharmacologically relevant concentrations, greater reduction to the parent amine occurred with DDS-NOH. Maintenance of MetHgb-forming potency was dependent on recycling with glutathione, but no difference in cycling efficiency was observed between DDS-NOH and SMX-NOH. In contrast, the pharmacodynamics of hydroxylamine-induced MetHgb formation were not changed by pretreatment with the glucose 6-phosphate dehydrogenase inhibitor epiandrosterone or by compounds that alter normal antioxidant enzyme activity. Methylene blue, which stimulates NADPH-dependent MetHgb reductase activity, decreased MetHgb levels but did not alter the differential potency of these hydroxylamines. DDS-NOH was also significantly more potent when incubated with purified human hemoglobin A0. Collectively, these data suggest that the inherently greater reactivity of DDS-NOH with hemoglobin, the greater conversion of DDS-NOH to its parent amine, and potential differences in disposition of hydroxylamine metabolites may contribute to the preferential development of dapsone-induced hemotoxicity and sulfamethoxazole-induced hypersensitivity reactions.
Footnotes
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Send reprint requests to: Craig K. Svensson, Pharm.D., Ph.D., Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202. E-mail:cks{at}wizard.pharm.wayne.edu
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↵1 This work was supported in part by National Institutes of Health Grant AI41395 (to C.K.S.). Portions of this work were presented at Experimental Biology ’98 in San Francisco, CA, April 20, 1998. T.P.R. was the recipient of an Advanced Predoctoral Fellowship in Pharmacology/Toxicology from the Pharmaceutical Researchers and Manufacturers of America Foundation (Washington, DC).
- Abbreviations:
- ADR
- adverse drug reactions
- AT
- 3-amino-1,2,4-triazole
- CDNB
- 1-chloro-2,4-dinitrobenzene
- DDS-NOH
- dapsone hydroxylamine
- DEM
- diethyl maleate
- EDU
- N-[2-(2-oxo-1-imidazolindinyl)-ethyl]-N′-phenylurea
- Emax
- maximum methemoglobin response (expressed as percent of hemoglobin present as MetHgb)
- EC50
- concentration causing 50%Emax
- EPI
- epiandrosterone
- G6PD
- glucose-6-phosphate dehydrogenase
- GSH
- reduced glutathione
- HPLC
- high-performance liquid chromatography
- MADDS-NOH
- monoacetyldapsone hydroxylamine
- MetHgb
- methemoglobin
- PBS
- phosphate-buffered saline
- RBC
- red blood cell
- SMX-NOH
- sulfamethoxazole hydroxylamine
- Received June 24, 1998.
- Accepted September 29, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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