Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone: Implications for differences in adverse drug reactions

Differences in the incidence of adverse drug reactions to trimethoprim-sulf amethoxazole and dapsone may result from differences in the formation, disp osition, toxicity, and/or detoxification of their hydroxylamine metabolites . In this study, we examine whether differences in the biochemical processi ng of sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (D DS-NOH) by erythrocytes [red blood cells (RBCs)] contribute to this differe ntial incidence. The methemoglobin (MetHgb)-forming capacity of both metabo lites was compared after a 60-min incubation with washed RBCs from four hea lthy human volunteers. DDS-NOH was significantly more potent (P = .004) but equally efficacious with SMX-NOH in its ability to form MetHgb. The elimin ation of potential differences in disposition by lysing RBCs did not change the MetHgb-forming potency of either hydroxylamine. At pharmacologically r elevant 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 betw een 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 a lter normal antioxidant enzyme activity. Methylene blue, which stimulates N ADPH-dependent MetHgb reductase activity, decreased MetHgb levels but did n ot alter the differential potency of these hydroxylamines. DDS-NOH was also significantly more potent when incubated with purified human hemoglobin A( o). Collectively, these data suggest that the inherently greater reactivity of DDS-NOH with hemoglobin, the greater conversion of DDS-NOH to its paren t amine, and potential differences in disposition of hydroxylamine metaboli tes may contribute to the preferential development of dapsone-induced hemot oxicity and sulfamethoxazole-induced hypersensitivity reactions.