Advertisement

Pharmaceutisch Weekblad

, Volume 13, Issue 5, pp 198–206 | Cite as

Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans

  • T. B. Vree
  • E. W. J. Beneken Kolmer
  • Y. A. Hekster
Articles

Abstract

Sulfamethomidine metabolism was studied in 6 volunteers. In humans, only N1-glucuronidation and N4-acetylation take place, leading to the final double conjugate N4-acetylsulfamethomidine N1-glucuronide. The N1-glucuronides were directly measured by high pressure liquid chromatography. Fast and slow acetylators show a similar half-life for sulfamethomidine (26±6 h) and its conjugates sulfamethomidine N1-glucuronide (26±6 h) and N4-acetylsulfamethomidine (36±16 h). Approximately 50–60% of the oral dose of sulfamethomidine is excreted in the urine, leaving 40–50% for excretion into bile and faeces. The main metabolite of sulfamethomidine is its N1-glucuronide, which accounts for 36±7% of the dose, followed by N4-acetylsulfamethomidine (16±8%). N1-glucuronidation results in a 75% decrease in protein binding of sulfamethomidine. N4-acetylsulfamethomidine and its N1-glucuronide showed the same high protein binding of 99%. The renal clearance of N4-acetylsulfamethomidine is 7.9±2.2 ml/min and approximately 20 times as high as that of the parent drug (0.46±0.16 ml/min). Total body clearance of sulfamethomidine is 4.5±0.9 ml/min and the volume of distribution in steady state 10.6±1.7 1. No measurable plasma concentrations of the N1-glucuronides from sulfamethomidine are found in plasma. This may be explained by renal glucuronidation after active tubular reabsorption.

Keywords

Clearance, renal Clinical trials Glucuronidation Metabolism Pharmacokinetics Protein binding Sulfamethomidine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cooper LZ, Madoff MA, Weinstein L. Absorption and excretion of sulfamethomidine, a ‘long-acting’ sulfonamide. Antibiot Chemother 1962;12:618–29.Google Scholar
  2. 2.
    DiCarlo FJ, Malament SG, Haynes LJ, Phillips GE. Metabolism of N1-(2-methyl-6-methoxy-4-pyrimidmyl)-sulfanilamide (sulfamethomidine) in man. Toxicol Appl Pharmacol 1963;5:61–70.Google Scholar
  3. 3.
    Matilla MJ, Takki S, Heino AE. Serum levels and urinary excretion of sulphamethomidine in the presence of other drugs. Scand J Clin Lab Invest 1970;25(Suppl 113):95.Google Scholar
  4. 4.
    Ueda M, Tsurui Y, Koizumi T. Studies on metabolism of drugs. XII. Quantitative separation of metabolites in human and rabbit urine after oral administration of sulfamonomethoxine and sulfamethomidine. Chem Pharm Bull 1972;20:2042–6.Google Scholar
  5. 5.
    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
  6. 6.
    DiCarlo FJ, Malament SG, Haynes LJ, Phillips GE. Metabolism of N1-(2-methyl-6-methoxy-4-pyrimidinyl)-sulfanilamide (sulfamethomidine) in the rat, the rabbit and the dog. Toxicol Appl Pharmacol 1962;4:475–88.Google Scholar
  7. 7.
    Padeiskaya EN, Polukhina LM, Pershin GN. Experimental study of sulformethoxine (Fanazyl) and sulfamethomidine (Methofadine). Farmakol Toksikol 1971;34:609–14.Google Scholar
  8. 8.
    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.Google Scholar
  9. 9.
    Bridges JW, Walker SR, Williams RT. Species differences and excretion of sulphasomidine and sulphamethomidine. Biochem J 1969;111:173–9.Google Scholar
  10. 10.
    Lee JN, Kjaersgaard P. Mammary and renal excretion of sulphamethomidine in cows. Nord Vet Med 1967;19:578–84.Google Scholar
  11. 11.
    Vree TB, Vree ML, Beneken Kolmer EWJ, Ross ME, Hekster YA, Shimoda M, et al. O-dealkylation and acetylation of sulfamethomidine by the snailCepaea hortensis. J Vet Pharmacol Ther 1989;12:344–7.Google Scholar
  12. 12.
    Vree TB, Klimowicz A, Vree JB, Shimoda M.O- dealkylation and acetylation of sulphamethomidine by the turtlePseudemys scripta elegans. Vet Quart 1990;12:60–3.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, Vree TB, Degen M, Mevius D. Pharmacokinetics of sulphamethoxazole in calves and cows. Vet Quart 1991;13:10–6.Google Scholar
  15. 15.
    Vree TB, Hekster YA. Clinical pharmacokinetics of sulfonamides revisited. Antibiot Chemother 1985;34:1–200.Google Scholar
  16. 16.
    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 Monitor 1986;8:434–9.Google Scholar
  17. 17.
    Vree TB, Hekster YA, Tijhuis MW, Termond EFS, Nouws JFM. Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5-hydroxy- and N4-acetyl metabolites in man. Biopharm Drug Dispos 1986;7:239–52.Google Scholar
  18. 18.
    Nouws JFM, Mevius D, Vree TB, Degen M. Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs. Vet Quart 1989;11: 78–87.Google Scholar
  19. 19.
    Vree TB, Vree ML, Nouws JFM. Acetylation and hydroxylation of sulfadimidine in the snailCepaea hortensis. J Vet Med 1986;33A:633–6.Google Scholar
  20. 20.
    Vree TB, Vree JB, Nouws JFM. Acetylation and hydroxylation of sulfadimidine by the turtleCuora amboniensis. J Vet Pharmacol Ther 1986;9:330–2.Google Scholar
  21. 21.
    Vree TB, Beneken Kolmer EWJ, Martea M, Bosch R. High performance liquid chromatography of sulfadimethoxine and its N1glueuronide, N4-acetyl-, and N4-acetyl-N1glucuronide metabolites in plasma and urine of man. J Chromatogr/Biomed Appl 1989;526: 119–28.Google Scholar
  22. 22.
    Bridges JW, Kibby MR, Walker SR, Williams RT. Species differences in the metabolism of sulphadimethoxine. Biochem J 1968;109:851–6.Google Scholar
  23. 23.
    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.Google Scholar
  24. 24.
    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.Google Scholar
  25. 25.
    Walker SR, Williams RT. The metabolism of sulphadimethoxypyrimidine. Xenobiotica 1972;2:69–75.Google Scholar
  26. 26.
    Vree TB, Beneken Kolmer EWJ, Martea M, Bosch R, Hekster YA, Shimoda M. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man. Pharm Weekbl [Sci] 1990;12:51–9.Google Scholar
  27. 27.
    Anonymous. SAS user's guide. Basics 1982 edition. Cary: SAS Institute, 1982.Google Scholar
  28. 28.
    Veng-Pedersen P. A simple method for obtaining the mean residence time of metabolites in the body. J Pharm Sci1986;75:818–9.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.Google Scholar
  30. 30.
    Vree TB, Beneken Kolmer EWJ, Hekster YA, Shimoda M, Ono M, Miura T. Pharmacokinetics, N1glucuronidation and N4-acetylation of sulfa-6-mono-methoxine in humans. Drug Metab Dispos 1990;18:852–8.Google Scholar
  31. 31.
    Vree TB, Vree JB, Beneken Kolmer N, Hekster YA, Shimoda M, Nouws JFM, et al. O-demethylation and N4-acetylation of sulfadimethoxine by the turtlePseudemys scripta elegans. Vet Quart 1989;11:138–43.Google Scholar
  32. 32.
    Takahashi Y. Mechanisms of nonlinear pharmacokinetics of sulfadimethoxine in cocks. Jpn J Vet Sci 1986;48:105–9.Google Scholar
  33. 33.
    Takahashi Y. Identification of desmethyl metabolite of sulfadimethoxine in chicken excreta. Jpn J Vet Sci 1986;48:999–1002.Google Scholar
  34. 34.
    Vree TB, Vree JB, Beneken Kolmer N, Hekster YA, Shimoda M, Nouws JFM, et al. O-demethylation and N4-acetylation of sulfadimethoxine by the snailCepaea hortensis. Jpn J Vet Sci 1989;51:364–8.Google Scholar
  35. 35.
    Shimoda M, Vree TB, Beneken Kolmer EWJ, Arts THM. The role of plasma protein binding on the metabolism and renal excretion of sulfadimethoxine and its metabolite N4-acetylsulfadimethoxine in pigs. Vet Quart 1990;12:87–98.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.Google Scholar
  37. 37.
    Rieder J. Physikalisch-chemische und biologische Untersuchungen an Sulfonamiden. Arzneimittelforsch 1963;13:84–9.Google Scholar
  38. 38.
    Van Ginneken CAM, Russel FGM. Saturable pharma cokinetics in the renal excretion of drugs. Clin Pharmacokinet 1989;16:38–54.Google Scholar
  39. 39.
    Siest G, Antoine B, Fournel S, Magdalou J, Thomassin J. The glucuronosyltransferases: what progress can pharmacologists expect from molecular biology and cellular enzymology. Biochem Pharmacol 1987;36:983–9.Google Scholar
  40. 40.
    Osborne R, Joel S, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990;47:12–9.Google Scholar
  41. 41.
    Sisenwine SF, Tio CO, Hadley FV, Lu AL, Kimmel B, Ruelius HW. Species related differences in the stereo selective glucuronidation of oxazepam. Drug Metab Dispos 1982;10:605–8.Google Scholar
  42. 42.
    Vree TB, Baars AM, Wuis EW. Direct high performance liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their cooresponding glucuronide conjugates. Pharm Weekbl [Sci] 1991;13:83–91.Google Scholar
  43. 43.
    Vree TB, Steegers-Theunissen RPM, Baars AM, Hekster YA. Direct high-performance liquid chromatographic analysis ofp-hydroxyphenyl-phenylhydantoin glucuronide, the final metabolite of phenytoin, in human serum and urine. J Chromatogr/Biomed Appl 1990;526:581–9.Google Scholar
  44. 44.
    Hyneck ML, Smith PC, Unseld E, Benet LZ. High-performance liquid chromatographic determination of tolmetin, tolmetin glucuronide and its isomeric conjugates in plasma and urine. J Chromatogr/Biomed Appl 1987;420:349–56.Google Scholar
  45. 45.
    Abshagen U, Betzien G, Endele R, Kaufmann B, Neugebauer G. Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration. Eur J Clin Pharmacol 1985;27:637–44.Google Scholar
  46. 46.
    Werner D, Martinez F, Roch-Ramel F. Urate andp- aminohippurate transport in the brush border membrane of the pig kidney. J Pharmacol Exp Ther 1990;252:792–9.Google Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1991

Authors and Affiliations

  • T. B. Vree
    • 1
  • E. W. J. Beneken Kolmer
    • 1
  • Y. A. Hekster
    • 1
  1. 1.Department of Clinical PharmacyUniversity Hospital Nijmegen Sint RadboudHB Nijmegenthe Netherlands

Personalised recommendations