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Sulfamethoxazole (SMX) hypersensitivity affects 20-50% of treated HIV patients. SMX-nitroso (SMX-NO), the cytotoxic metabolite thought to mediate these reactions, is non-enzymatically reduced by ascorbate (AA). The purpose of these studies was to determine the relationship between intracellular AA deficiency (reported in HIV-infection) and in vitro cytotoxicity in the presence of SMX metabolites (which has been used as a marker for sulfonamide hypersensitivity). Peripheral blood mononuclear cells (PBMC) were obtained from HIV-positive patients and healthy controls. PBMC AA concentrations and SMX-NO reduction were determined by HPLC. PBMC from each subject were also exposed to 0.1-1.0 mM SMX-NO for 2 h., followed by overnight incubation in media. Cytotoxicity was quantified using YO-PRO-1®fluorescence. In preliminary results from 22 subjects, intracellular AA was strongly correlated with PBMC reduction of SMX-NO (r=0.73; P=0.0001). In addition, AA was depleted during exposure to SMX-NO, with a strong linear correlation between nmoles SMX-NO reduced and nmoles AA depleted (r=0.75; P<0.0001). There was a trend toward an inverse relationship between intracellular AA and cytotoxicity (r= -0.31; P=0.18), and between SMX-NO reduction and cytotoxicity (r= -0.36; P=0.14), but the association was not significant in this preliminary sample. Additional patient recruitment is underway to further characterize the relationship between ascorbate deficiency and sulfonamide toxicity.Clinical Pharmacology & Therapeutics (2004) 75, P15–P15; doi: 10.1016/j.clpt.2003.11.056