Formation and elimination of sulphamethoxazole hydroxylamine after oral administration of sulphamethoxazole.

The formation and elimination of sulphamethoxazole hydroxylamine in relation to the pharmacokinetics of the parent compound and its N4-acetyl metabolite were investigated in six healthy subjects after a single oral dose of 800 mg sulphamethoxazole. The apparent half-lives of sulphamethoxazole and its metabolites were approximately 10 h, indicative of formation rate-limited metabolism. The mean residence time of the hydroxylamine metabolite was 5.5 +/- 1.5 h. The renal clearance of sulphamethoxazole hydroxylamine was 4.39 +/- 0.91 l h-1. The urinary recovery of sulphamethoxazole accounted for 16.5 +/- 5.5% of the dose, N4-acetyl-sulphamethoxazole for 46.2 +/- 6.6% and the hydroxylamine metabolite for 2.4 +/- 0.8%. The remaining 35% of the dose was unaccounted for. Acetylator phenotype was determined using sulphadimidine. The renal excretion of sulphamethoxazole hydroxylamine was 1.9 +/- 0.9% in slow acetylators (n = 3) and 2.8 +/- 0.3% in fast acetylators (n = 3); for N4-acetyl-sulphamethoxazole the values were 48 +/- 6% and 44 +/- 8%, respectively. Sulphamethoxazole is metabolized, although to a limited extent, to a hydroxylamine metabolite. This metabolite may be important for the pathogenesis of adverse reactions.