The incidence of adverse reactions to
sulfamethoxazole-
trimethoprim (SMX-
TMP) combination products is higher in patients with
AIDS than in the general population. Idiosyncratic adverse reactions to SMX are believed to be dependent upon the formation of the reactive intermediate,
sulfamethoxazole hydroxylamine (
SMX-HA), and its further oxidation product, nitroso-SMX. Changes in the disposition of SMX have been proposed to contribute to the increased risk of SMX adverse reactions in patients with
AIDS. Activation of host defense mechanisms is known to alter
drug metabolism and could decrease the enzymatic reduction of
SMX-HA to the parent SMX, causing an imbalance in bioactivation and detoxification. We tested this hypothesis in a rat model of
lipopolysaccharide (LPS)-evoked host defense activation. Rats were treated i.p. with 1 mg/kg of LPS, and hepatic microsomes were isolated 24 hr
after treatment. The bioactivation of SMX to
SMX-HA was reduced 50% by pretreatment with LPS (113 +/- 10 vs 65 +/- 4 pmol/min/mg; P < 0.05). However, the
NADH-dependent reduction of
SMX-HA to SMX was reduced by over 80% (454 +/- 90 vs 81 +/- 48 pmol/min/mg; P < 0.05). A decreased ability to reduce
SMX-HA to SMX could predispose patients with systemic activation of host defense mechanisms, such as those with
AIDS, to the occurrence of SMX-associated adverse reactions.