title: Formation and elimination of sulphamethoxazole hydroxylamine after oral administration of sulphamethoxazole.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Academic Hospital Nijmegen St Radboud, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: M A
authors.initials: MA
authors.lastname: Mantel
authors.forename: T B
authors.initials: TB
authors.lastname: Vree
authors.forename: P P
authors.initials: PP
authors.lastname: Koopmans
authors.forename: J W
authors.initials: JW
authors.lastname: van der Meer
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D013420:Sulfamethoxazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D044465:White People
chemical_list: C059873:sulfamethoxazole hydroxylamine; D013420:Sulfamethoxazole