Pharmaceutisch Weekblad

, Volume 12, Issue 2, pp 51–59 | Cite as

Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man

  • T. B. Vree
  • E. W. J. Beneken Kolmer
  • M. Martea
  • R. Bosch
  • Y. A. Hekster
  • M. Shimoda
Original Articles


Sulfadimethoxine is metabolized byO-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8±4.2 h versus 36.3±5.4 h; P=0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3±5.2 h versus 53.5±8.5 h, P=0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50–60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40–50% for excretion into bile and faeces.


Chromatography, high pressure liquid Clearance Metabolism Pharmacokinetics Protein binding Sulfadimethoxine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vree TB, Reekers-Ketting JJ, Hekster YA, Nouws JFM. Acetylation and deacetylation of sulphonamides in dogs. J Vet Pharmacol Ther 1983;6:153–6.PubMedGoogle Scholar
  2. 2.
    Baggot D. Pharmacokinetics of sulfadimethoxine in cats. Aust J Exp Biol Med Sci 1977;55:663–70.PubMedGoogle Scholar
  3. 3.
    Bajwa RS, Singh J. Studies on the levels of sulphadimethoxine and sulphamethoxypyridazine in blood of poultry. Ind J Animal Sci 1977;47:549–53.Google Scholar
  4. 4.
    Onodera T, Inoue S, Kasahara A, Oshima Y. Experimental studies on sulfadimethoxine in fowls. Jpn J Vet Sci 1970;32:275–83.Google Scholar
  5. 5.
    Oshima Y, Kasahara A, Onodera M. Experimental studies on sulfadimethoxine in fowls. Plasma concentration in hens after oral administration. Jpn J Vet Sci 1964;26:115–20.Google Scholar
  6. 6.
    Caldwell J, Williams RT, Bassir O, French MR. Drug metabolism in exotic animals. Eur J Drug Metab Pharmacokinet 1978;2:67–71.Google Scholar
  7. 7.
    French MR, Bababunmi EA, Golding RR, et al. The conjugation of phenol, benzoic acid, 1-naphthylacetic acid and sulphadimethoxine in the lion, civet and genet. FEBS Lett 1974;46:134–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Barron MG, Gedutis C, James MO. Pharmacokinetics of sulphadimethoxine in the lobsterHomarus americanus following intrapericardial administration. Xenobiotica 1988;18:269–76.PubMedGoogle Scholar
  9. 9.
    Shimoda M, Vree TB, Beneken Kolmer EWJ, Arts ThHM. The role of plasma protein binding on the metabolism and renal excretion of sulfadimethoxine and its metabolite N4-acetylsulfadimethoxine in pigs. Vet Quart (in press).Google Scholar
  10. 10.
    Adamson RH, Bridges JW, Kibby MR, Walker SR, Williams RT. The fate of sulphadimethoxine in primates compared with other species. Biochem J 1970;118:41–5.PubMedGoogle Scholar
  11. 11.
    Boxenbaum HG, Pellig J, Hanson LJ, Snyder WE, Kaplan SA. Pharmacokinetics of sulphadimethoxine in cattle. Res Vet Sci 1977;23:24–8.PubMedGoogle Scholar
  12. 12.
    Vree TB, Hekster YA, Tijhuis MW, Baakman M, Oosterbaan MJM, Termond EFS. Effects of methoxy groups in the N1-substituent of sulfonamides on the pathways of elimination in man. Pharm Weekbl [Sci] 1984;6:150–6.Google Scholar
  13. 13.
    Vree TB, Hekster YA. Clinical pharmacokinetics of sulfonamides and their metabolites. Antibiot Chemother 1987;37:25–30.Google Scholar
  14. 14.
    Nouws JFM, Firth EC, Vree TB, Baakman M. Pharmacokinetics and renal clearance of sulfamethazine, sulfamerazine and sulfadiazine and their N4-acetyl and hydroxy metabolites in horses. Am J Vet Res 1987;48:392–402.PubMedGoogle Scholar
  15. 15.
    Nouws JFM, Mevius D, Vree TB, Degen M. Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulfadiazine and their N4-acetyl and hydroxy metabolites in pigs. Vet Quart 1989;11:78–87.Google Scholar
  16. 16.
    Vree TB, Hekster YA. Clinical pharmacokinetics of sulfonamides. Revisited. Antibiot Chemother 1985;34:1–200.PubMedGoogle Scholar
  17. 17.
    Vree TB, Hekster YA, Nouws JFM, Baakman M. Pharmacokinetics, metabolism and renal excretion of sulfadimidine and its N4-acetyl and hydroxy metabolites in man. Ther Drug Monit 1986;8:434–9.PubMedGoogle Scholar
  18. 18.
    Vree TB, Vree JB, Beneken Kolmer N, et al.O-Demethylation and N4-acetylation of sulfadimethoxine by the turtlePseudemys scripta elegans. Vet Quart 1989;11:138–43.Google Scholar
  19. 19.
    Vree TB, Vree JB, Beneken Kolmer N, et al.O-Demethylation and N4-acetylation of sulfadimethoxine by the snailCepaea hortensis. Jpn J Vet Sci 1989;51:364–8.Google Scholar
  20. 20.
    Bridges JW, Kibby MR, Walker SR, Williams RT. Species differences in the metabolism of sulphadimethoxine. Biochem J 1968;109:851–6.PubMedGoogle Scholar
  21. 21.
    Uno T, Kushima T, Fujimoto M. Studies on the metabolism of sulfadimethoxine. I. On the excreted substance in the human urine after oral administration of sulfadimethoxine. Chem Pharm Bull 1965;13:261–7.PubMedGoogle Scholar
  22. 22.
    Uno T, Kushima T, Hiraoka T. Studies on the metabolism of sulfadimethoxine. II. Determinations of metabolites in human and rabbit urine after oral administration of sulfadimethoxine. Chem Pharm Bull 1967;15:1272–6.PubMedGoogle Scholar
  23. 23.
    Walker SR, Williams RT. The metabolism of sulphadimethoxypyrimidine. Xenobiotica 1972;2:69–75.PubMedGoogle Scholar
  24. 24.
    Vree TB, Beneken Kolmer EWJ, Martea M, Bosch R. High performance liquid chromatography of sulfadimethoxine and its N1-glucuronide, N4-acetyl-, and N4-acetyl-N1-glucuronide metabolites in plasma and urine of man. J Chromatogr 1990;526:119–28.PubMedGoogle Scholar
  25. 25.
    Anonymous. SAS user's guide. Basics 1982 edition. Cary: SAS Institute Inc., 1982.Google Scholar
  26. 26.
    Veng-Pedersen P. A simple method for obtaining the mean residence time of metabolites in the body. J Pharm Sci 1986;75:818–9.PubMedGoogle Scholar
  27. 27.
    Takahashi Y. Mechanisms of nonlinear pharmacokinetics of sulfadimethoxine in cocks. Jpn J Vet 1986;48:105–9.Google Scholar
  28. 28.
    Takahashi Y. Identification of desmethyl metabolite of sulfadimethoxine in chicken excreta. Jpn J Vet Sci 1986;48:999–1002.Google Scholar
  29. 29.
    Bridges JW, Kibby MR, Williams RT. The structure of the glucuronide of sulphadimethoxine formed in man. Biochem J 1965;96:829–36.PubMedGoogle Scholar
  30. 30.
    Skachilova SY, Shramova ZI, Voronin VG, Petrugova NP, Ovchinnikova AM, Sheinker YN. Study of the conditions of the formation of impurities in technical sulfadimethoxine. Khimiko Farmatsevticheskii Zhurnal 1987;21:481–4.Google Scholar
  31. 31.
    Caldwell J. The significance of phase II (conjugation) reactions in drug disposition and toxicity. Life Sci 1979;24:571–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Ahmad B, Powell JW. N1-Glucosides as urinary metabolites of sulphadimidine, sulphamerazine and sulphamethoxazole. Eur J Drug Metab Pharmacokinet 1988;13:177–83.PubMedGoogle Scholar
  33. 33.
    Hirom PC, Millburn P, Smith RL, Williams RT. Molecular weight and chemical structure as factors in the biliary excretion of sulphonamides in the rat. Xenobiotica 1972;2:205–14.PubMedGoogle Scholar
  34. 34.
    Yagi N, Agata I, Kawamura T, et al. Fundamental pharmacokinetic behavior of sulfadimethoxine, sulfamethoxazole and their biotransformed products in dogs. Chem Pharm Bull 1981;29:3741–7.PubMedGoogle Scholar
  35. 35.
    Van Ginneken CAM, Russel FGM. Saturable pharmacokinetics in the renal excretion of drugs. Clin Pharmacokinet 1989;16:38–54.Google Scholar
  36. 36.
    Hubbard JW, Briggs CJ, Savage C, Smith D. Binding of sulfadimethoxine to isolated human blood protein fractions. J Pharm Sci 1984;73:1319–22.PubMedGoogle Scholar
  37. 37.
    Rieder J. Physikalisch-chemische und biologische Untersuchungen an Sulfonamiden. Arzneimittelforsch 1963;13:84–9.Google Scholar
  38. 38.
    Arita T, Hori R, Takada M, Misawa A. Transformation and excretion of drugs in biological systems. V. Correlation between renal excretion and biotransformation of sulfadimethoxine. Chem Pharm Bull 1971;19:930–6.PubMedGoogle Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1990

Authors and Affiliations

  • T. B. Vree
    • 1
  • E. W. J. Beneken Kolmer
    • 2
  • M. Martea
    • 2
  • R. Bosch
    • 2
  • Y. A. Hekster
    • 2
  • M. Shimoda
    • 3
  1. 1.Department of Clinical Pharmacy and Department of AnaesthesiologyUniversity Hospital NijmegenHB NijmegenThe Netherlands
  2. 2.Department of Clinical PharmacyUniversity Hospital NijmegenHB NijmegenThe Netherlands
  3. 3.Department of Veterinary MedicineTokyo University of Agriculture and TechnologyTokyoJapan

Personalised recommendations