THE EFFECT OF FLUCONAZOLE AND KETOCONAZOLE ON THE METABOLISM OF SULFAMETHOXAZOLE

1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hyd roxylamine has been implicated in the hypersensitivity reactions assoc iated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency o f toxicity which is observed in HIV-infected patients. Therefore, in t his study, we have investigated the ability of fluconazole and ketocon azole, known cytochrome P450 inhibitors, to inhibit the formation of s ulphamethoxazole hydroxylamine. 2 Ten healthy male volunteers were giv en co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) a lone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week betw een each phase. Urine was collected for 24 h, and sulphamethoxazole an d its metabolites were quantified by electrospray LC-MS. 3 Ketoconazol e had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly (P < 0.001) i nhibited the formation of sulphamethoxazole hydroxylamine by 50.0 +/- 15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole t o the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9 +/- 15.8% and 64.0 +/- 12.0%, respectively, but had no effect on the a mount of sulphamethoxazole, N-4-acetyl sulphamethoxazole, or sulphamet hoxazole N,glucuronide excreted in urine. 4 The potential clinical ben efit of using fluconazole to prevent hypersensitivity to co-trimoxazol e in patients with AIDS needs to be assessed in a prospective study us ing both metabolite formation and the clinical occurrence of adverse r eactions as end-points.