Effect of lipopolysaccharide (LPS)-evoked host defense activation on hepatic microsomal formation and reduction of sulfamethoxazole hydroxylamine in the rat

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.