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

Cribb, AE McQuaid, T Renton, KW

Ae. Cribb et al., Effect of lipopolysaccharide (LPS)-evoked host defense activation on hepatic microsomal formation and reduction of sulfamethoxazole hydroxylamine in the rat, BIOCH PHARM, 62(4), 2001, pp. 457-459

11

INGLESE

Article

Pharmacology & Toxicology

BIOCHEMICAL PHARMACOLOGY

0006-2952 → ACNP

62

4

2001

457 - 459

ISI

0006-2952(20010815)62:4<457:EOL(HD>2.0.ZU;2-J

The incidence of adverse reactions to sulfamethoxazole-trimethoprim (SMX-TM P) combination products is higher in patients with AIDS. than in the genera l population. Idiosyncratic adverse reactions to SMX are believed to be dep endent upon the formation of the reactive intermediate, sulfamethoxazole hy droxylamine (SMX-HA), and its further oxidation product, nitroso-SMX. Chang es in the disposition of SMX have been proposed to contribute to the increa sed risk of SMX adverse reactions in patients with AIDS. Activation of host defense mechanisms is known to alter drug metabolism and could decrease th e 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 treat ed i.p. with 1 mg/kg of LPS, and hepatic microsomes were isolated 24 hr aft er treatment. The bioactivation of SMX to SMX-HA was reduced 50% by pretrea tment 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 defens e mechanisms, such as those with AIDS, to the occurrence of SMX-associated adverse reactions. (C) 2001 Elsevier Science Inc. All rights reserved.