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. 1994 Aug;38(2):147–150. doi: 10.1111/j.1365-2125.1994.tb04339.x

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

A J van der Ven 1, M A Mantel 1, T B Vree 1, P P Koopmans 1, J W van der Meer 1
PMCID: PMC1364861  PMID: 7981016

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.

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Selected References

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  1. Buhl R., Jaffe H. A., Holroyd K. J., Wells F. B., Mastrangeli A., Saltini C., Cantin A. M., Crystal R. G. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989 Dec 2;2(8675):1294–1298. doi: 10.1016/s0140-6736(89)91909-0. [DOI] [PubMed] [Google Scholar]
  2. Cribb A. E., Miller M., Leeder J. S., Hill J., Spielberg S. P. Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity. Drug Metab Dispos. 1991 Sep-Oct;19(5):900–906. [PubMed] [Google Scholar]
  3. Cribb A. E., Spielberg S. P. Sulfamethoxazole is metabolized to the hydroxylamine in humans. Clin Pharmacol Ther. 1992 May;51(5):522–526. doi: 10.1038/clpt.1992.57. [DOI] [PubMed] [Google Scholar]
  4. Gordin F. M., Simon G. L., Wofsy C. B., Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1984 Apr;100(4):495–499. doi: 10.7326/0003-4819-100-4-495. [DOI] [PubMed] [Google Scholar]
  5. Perry S., Ryan J., Ashman T., Jacobsberg L. Refusal of zidovudine by HIV-positive patients. AIDS. 1992 May;6(5):514–515. [PubMed] [Google Scholar]
  6. Proost J. H., Meijer D. K. MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Comput Biol Med. 1992 May;22(3):155–163. doi: 10.1016/0010-4825(92)90011-b. [DOI] [PubMed] [Google Scholar]
  7. Rieder M. J., Shear N. H., Kanee A., Tang B. K., Spielberg S. P. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther. 1991 Jan;49(1):13–17. doi: 10.1038/clpt.1991.3. [DOI] [PubMed] [Google Scholar]
  8. Rieder M. J., Uetrecht J., Shear N. H., Cannon M., Miller M., Spielberg S. P. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites. Ann Intern Med. 1989 Feb 15;110(4):286–289. doi: 10.7326/0003-4819-110-4-286. [DOI] [PubMed] [Google Scholar]
  9. Rieder M. J., Uetrecht J., Shear N. H., Spielberg S. P. Synthesis and in vitro toxicity of hydroxylamine metabolites of sulfonamides. J Pharmacol Exp Ther. 1988 Feb;244(2):724–728. [PubMed] [Google Scholar]
  10. Shear N. H., Spielberg S. P., Grant D. M., Tang B. K., Kalow W. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986 Aug;105(2):179–184. doi: 10.7326/0003-4819-105-2-179. [DOI] [PubMed] [Google Scholar]
  11. Shear N. H., Spielberg S. P. In vitro evaluation of a toxic metabolite of sulfadiazine. Can J Physiol Pharmacol. 1985 Nov;63(11):1370–1372. doi: 10.1139/y85-225. [DOI] [PubMed] [Google Scholar]
  12. Vree T. B., Hekster Y. A. Clinical pharmacokinetics of sulfonamides and their metabolites: an encyclopedia. Antibiot Chemother (1971) 1987;37:1–214. [PubMed] [Google Scholar]
  13. Vree T. B., O'Reilly W. J., Hekster Y. A., Damsma J. E., van der Kleijn E. Determination of the acetylator phenotype and pharmacokinetics of some sulphonamides in man. Clin Pharmacokinet. 1980 May-Jun;5(3):274–294. doi: 10.2165/00003088-198005030-00006. [DOI] [PubMed] [Google Scholar]
  14. van der Ven A. J., Koopmans P. P., Vree T. B., van der Meer J. W. Adverse reactions to co-trimoxazole in HIV infection. Lancet. 1991 Aug 17;338(8764):431–433. doi: 10.1016/0140-6736(91)91046-w. [DOI] [PubMed] [Google Scholar]

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