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Vol. 282, Issue 2, 795-801, 1997
Department of Pharmacology and Therapeutics, The University of
Liverpool, Liverpool, United Kingdom
Idiosyncratic toxicity associated with sulfamethoxazole (SMX) is
thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). To establish the link
between the formation of the ultimate reactive metabolite and SMX
hypersensitivity, we have undertaken metabolism and immunogenicity studies in the rat by use of SMX and its metabolites. SMX was excreted
in urine as N4-acetyl SMX and SMX-NOH, with
~10% remaining unchanged as parent amine. After administration of
SMX-NOH (54 mg·kg
1) and SMX-NO (10 mg·kg1), 38.3% and 46.1% of the doses,
respectively, were excreted in urine as SMX and
N4-acetyl SMX, which indicated extensive
reduction of these metabolites in vivo. The immunogenic
potential of SMX and its metabolites, SMX-NOH and SMX-NO, were assessed
in rats by analyzing serum samples for the presence of anti-SMX IgG
antibodies during a 4-week dosing period. No antibodies to SMX were
detected in either control or SMX-treated rats. In contrast, a high
titer of SMX-specific IgG antibody was present in sera from all the rats administered SMX-NO, reaching a maximum 14 to 21 days after the
initial dose. Rats administered SMX-NOH only produced a weak IgG
response after 3 weeks of dosing. These findings indicate that SMX-NO
is highly immunogenic and may be responsible for the hypersensitivity
reactions associated with SMX. Both SMX-NOH and SMX-NO undergo
extensive reduction in vivo which may afford protection against SMX toxicity.
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