The relationship between the disposition and immunogenicity of sulfamethoxazole in the rat.
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 approximately 10% remaining unchanged as parent amine. After administration of SMX-NOH (54 mg x kg(-1)) and SMX-NO (10 mg x kg(-1)), 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.
Gill
H J
HJ
Department of Pharmacology and Therapeutics, The University of Liverpool, United Kingdom.
Hough
S J
SJ
Naisbitt
D J
DJ
Maggs
J L
JL
Kitteringham
N R
NR
Pirmohamed
M
M
Park
B K
BK
D000818:Animals; D000918:Antibody Specificity; D001711:Biotransformation; D004342:Drug Hypersensitivity / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013420:Sulfamethoxazole / Q000276:immunology / Q000493:pharmacokinetics* / Q000652:urine
D007074:Immunoglobulin G; D013420:Sulfamethoxazole