Sulfamethoxazole reactive metabolite

Cribb AE, Nuss CE, Alberts DW, et al. Covalent binding of sulfamethoxazole reactive metabolites to human and rat liver subcellular fractions assessed by immunochemical detection. Chem Res Toxicol 1996 9(2) 500-507. 

FIGURE 8.4 Sulfamethoxazole cannot readily form a nitrenium ion and the major reactive metabolite is the nitroso metabolite. 

Hess DA, Sisson ME, Suria H, et al. Cytotoxicity of sulfonamide reactive metabolites Apoptosis and selective toxicity of CD8(+) cells by the hydroxylamine of sulfamethoxazole. FASEB J. 1999 13(13) 1688-1698. 

Fig. 6.12 Bioactivation of sulfamethoxazole to its reactive metabolite and subsequent steps leading to the metabolite-specific immune response and hypersensitivity/tissue damage...

Sometimes, as with sulfamethoxazole, the drug itself does not react with proteins or peptides to induce an immune response. Rather, intracellular metabolism of the parent drug forms the metabolite, sulfamethoxazole-nitroso, which binds covalently to proteins and peptides and induces immunogenicity [41]. This represents a drug that is a pro-hapten, which is immunologically reactive and able to bind to MHC complexes on APCs only after it is metabohzed. 

Immunologic Cross-reactivity between sulfamethoxazole and sulfasalazine has been studied using in vitro lymphocyte transformation responses in five subjects with severe allergies to either drug (2 and 3 subjects respectively) [124 "]. In all cases lymphocyte transformation was positive to both sulfamethoxazole and sulfapyridine (a metabolite of sulfasalazine), but not to the related non-aromatic sulfonamides furosemide and hydrochlorothiazide. Cross-reactivity can occur between sulfonamide antibiotics and non-antibiotics when there is structural similarity. 

The rate of drug-induced adverse reactions in HIV-infected patients is over five times higher than the rate for HIV-negative subjects, and although the reason for this is not known, some observations related to reduction of the reactive nitroso-sulfamethoxazole metabolite may be pertinent. Deficiencies of ascorbate and thiols (for example glutathione), two agents that effect reduction of the metabolite in vivo, have been reported in HIV-infected subjects and it has been speculated that this may result in increased metabolite-mediated lymphocyte toxicity and a significantly increased risk of hypersensitivity reactions. 

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