European Journal of Clinical Pharmacology

, Volume 4, Issue 4, pp 233–240 | Cite as

Sulphamethoxazole/trimethoprim: Pharmacokinetic studies in patients with chronic renal failure

  • R. Baethke
  • G. Golde
  • G. Gahl


The pharmacokinetics of sulphamethoxazole (SMZ) and trimethoprim (TMP) have been investigated in four healthy volunteers, 15 patients with stable chronic renal failure and 3 patients on regular dialysis. The dosage schedule was 400 mg of SMZ and 80 mg of TMP orally every 12 h. The plasma concentrations and urinary excretion have been analysed in terms of a one compartment open model, allowing for elimination by renal excretion and metabolic processes. — At equilibrium the plasma concentrations of unchanged sulphonamide showed no significant correlation with the degree of renal impairment. The accumulation of TMP increased slightly without affecting the concentration ratio of both agents in plasma. In contrast, increasing accumulation of metabolized SMZ was demonstrated in the presence of renal insufficiency. Indirect evidence indicates that rising metabolite levels under these circumstances may lead to a displacement of unchanged sulphonamide from protein binding sites. — The cumulative urinary excretion amounted to 82.4% of the dose of sulphonamide administered, which probably corresponds to the fraction of the compound absorbed. The urinary concentration of biologically active SMZ was slightly below the plasma level, especially in advanced renal failure, but it remained above the minimum inhibitory concentrations reported in the literature. The concentration of TMP in urine was considerably higher than in plasma, it decreased with loss of renal function as did active SMZ.

Key words

Sulphamethoxazole trimethoprim pharmacokinetics uraemia sulphonamides 


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  1. 1.
    Alfthan, O., Liewendahl, K., Ervast, H.S.: Importance of temperature for the diagnosis of sulphonamide crystalluria in man. Ann. clin. Res.1, 177–181 (1969).Google Scholar
  2. 2.
    Boxer, G.E., Jellinek, V.C.: Streptomycin in the blood: Chemical determinations after single and repeated intramuscular injections. J. Pharmacol exp. Ther.92, 226–235 (1948).Google Scholar
  3. 3.
    Bünger, P., Diller, W., Führ, J., Krüger-Thiemer, E.: Vergleichende Untersuchungen an neueren Sulfanilamiden. Arzneimittel-Forsch.11, 247–255 (1961).Google Scholar
  4. 4.
    Büttner, H., Portwich, F., Manzke, R., Staudt, N.: Zur Pharmakokinetik von Sulfonamiden unter pathologischen Bedingungen. Klin. Wschr.42, 103–108 (1964).Google Scholar
  5. 5.
    Dettli, L., Spring, P., Habersang, R.: Drug dosage in patients with impaired renal function. Postgrad. med. J. Suppl.46, 32–35 (1970).Google Scholar
  6. 6.
    — Pharmakokinetik bei repetierter Arzneimittelapplikation: Kumulationslehre. In: Kuemmerle, H.P., Garrett, E.R., Spitzky, K.H.: Klinische Pharmakologie und Pharmakotherapie. München: Urban & Schwarzenberg 1971.Google Scholar
  7. 7.
    Dornbusch, K.: Regression line analysis of the synergistic effect for the combination of trimethoprim/sulphamethoxazole. Chemotherapy16, 229–238 (1971).Google Scholar
  8. 8.
    Dost, F.H.: Grundlagen der Pharmakokinetik. 2. Auflage. Stuttgart: Thieme-Verlag 1968.Google Scholar
  9. 9.
    Goff, J.B., Schlegel, J.U., O'Dell, R.M.: Urinary excretion of nalidixic acid, sulfamethizole, and nitrofurantoin with reduced renal function. J. Urol.99, 371–375 (1968).Google Scholar
  10. 10.
    Hierholzer, K., Butz, M., Baethke, R.: Evaluation of measurement for reduced glomerular filtration rate in the severely diseased kidney. Communication Int. Symp. on Uraemia, Freiburg 1971 (in press).Google Scholar
  11. 11.
    Hitzenberger, G., Korn, A., Kotzaurek, R., Schmidt, P., Deutsch, E.: Pharmakokinetik von Trimethoprim und Sulfamethoxazol bei Patienten mit schwerster renaler Eliminationsstörung und Hämodialyse. Communication 8. Symp. Ges. f. Nephrologie, Aachen 1971 (in press).Google Scholar
  12. 12.
    Höffler, D., Meyer, A., Scheler, F.: Blut- und Harnspiegel des Sulfamethoxydiazin (Durenat®) bei eingeschränkter Nierenfunktion. Med. Welt1966, 1367–1372.Google Scholar
  13. 13.
    Knight, G.J.: Kinetic studies with a trimethoprim/sulphonamide combination. 5. Int. Congr. Chemotherapy. Vol. I, 1, Wien 1969.Google Scholar
  14. 14.
    Krüger-Thiemer, E., Bünger, P.: Evaluation of the risk of cristalluria with sulfa drugs. Proc. Europ. Soc. Study drug Toxicity6, 185–207 (1965).Google Scholar
  15. 15.
    — Application of kinetic analysis for calculation of dosage regimens. In: Siegler, P.E., Moyer, J.H. III, Animal and clinical pharmacologic techniques in drug evaluation, Vol. II, Year Book Med. Publ., Chicago 1967.Google Scholar
  16. 16.
    Lipmann, R.W., Marti, H.V.: Effect of renal function on excretion of sulfadimetine given in small doses for urinary infection. J. Urol.70, 548–551 (1953).Google Scholar
  17. 17.
    Lubowitz, H., Slatopolski, E., Shankel, S., Rieselbach, R. E., Bricker, N.S.: Glomerular filtration rate: determination in patients with chronic renal disease. J. Amer. med. Ass.199, 252–256 (1967).Google Scholar
  18. 18.
    Nelson, E., O'Reilly, S.: Kinetics of sulfisoxazole acetylation and excretion in humans. J. Pharmacol. exp. Ther.129, 368–372 (1960).Google Scholar
  19. 19.
    Orr, J.S., Shimmins, J., Speirs, C.F.: Method for estimating individual drug-dosage regimens. Lancet1969 II, 771–773.Google Scholar
  20. 20.
    Reber, H., Wild, F., Paris, J.: Experimentelle Daten über das neue Sulfonamid 5-Methyl-3-sulfanilamidoisoxazol (Ro 4-2130) beim Erwachsenen. Chemotherapia6, 273–284 (1963).Google Scholar
  21. 21.
    Reeves, D.S.: Sulphamethoxazole/trimethoprim: the first two years. Clin. Path.24, 430–437 (1971).Google Scholar
  22. 22.
    Reidenberg, M.M., Kostenbauder, H., Adams, W.P.: Rate of drug metabolism in obese volunteers before and during starvation and in azotemic patients. Metabolism18, 209–213 (1969).Google Scholar
  23. 23.
    Rieder, J.: Physikalisch-chemische und biologische Untersuchungen an Sulfonamiden. Arzneimittel-Forsch.13, 81–88 (1963).Google Scholar
  24. 24.
    — Quantitative determination of the bacteriostatically active fraction of sulfonamides and the sum of their inactive metabolites in the body fluids. Chemotherapy17, 1–21 (1972).Google Scholar
  25. 25.
    - Fernex, M., Schwartz, D.E.: Pharmacokinetic data on the combination sulfamethoxazole plus trimethoprim in patients with renal impairment. Communication VII. Int. Congr. Chemotherapy, Prague 1971.Google Scholar
  26. 26.
    Schwartz, D.E., Koechlin, B.A., Weinfeld, R.E.: Spectrofluorometric method for the determination of trimethoprim in body fluids. Chemotherapy, Suppl.14, 22–29 (1969).Google Scholar
  27. 27.
    — Ziegler, W.H.: Assay and pharmacokinetics of trimethoprim in man and animal. Postgrad. Med. J., Suppl.45, 32–37 (1969).Google Scholar
  28. 28.
    Sharpstone, P.: The renal handling of trimethoprim and sulphamethoxazole in man. Postgrad. Med. J., Suppl.45, 38–45 (1969).Google Scholar
  29. 29.
    Wagner, J.G., Northam, J.J., Alway, C.D., Carpenter, O.S.: Blood levels of drug at the equilibrium state after multiple dosing. Nature (Lond.)207, 1301–1302 (1965).Google Scholar
  30. 30.
    — Theory and practice of adjusting dosage of drugs on the basis of endogenous creatinine clearance or serum creatinine concentration. In: Biopharmaceutics and relevant pharmacokinetics. Hamilton: Drug Intelligence Publ. 1971.Google Scholar
  31. 31.
    Westlake, W.J.: Problems associated with analysis of pharmacokinetic models. J. pharmaceut. Sci.60, 882–885 (1971).Google Scholar
  32. 32.
    Williams, D.M., Wimpenny, J., Assher, A.W.: Renal clearance of sodium sulphadimidine in normal and uraemic subjects. Lancet1968 II, 1058–1060.Google Scholar
  33. 33.
    von Wittenau, M.S., Yeary, R.: The excretion and distribution in body fluids of tetracyclines after intravenous administration to dogs. J. Pharmacol. exp. Ther.140, 258–266 (1963).Google Scholar

Copyright information

© Springer-Verlag 1972

Authors and Affiliations

  • R. Baethke
    • 1
    • 2
  • G. Golde
    • 1
    • 3
  • G. Gahl
    • 1
    • 2
  1. 1.Klinikum WestendFree University of BerlinGermany
  2. 2.Department of MedicineRenal DivisionGermany
  3. 3.Department of RadiologyBiophysical LaboratoriesGermany

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