Clinical Pharmacokinetics

, Volume 3, Issue 5, pp 369–380 | Cite as

Clinical Pharmacokinetics of Phenylbutazone

  • Jarle Aarbakke


More than 25 years after Phenylbutazone was introduced as a non-steroidal anti-inflammatory agent, basic knowledge is still accumulating on its pharmacokinetics in man. Phenylbutazone is almost completely absorbed after oral administration. A large fraction of the drug in plasma is bound to proteins, and the drug has a small volume of dislribution. Phenylbutazone is eliminated by metabolism, only 1% being excreted unchanged in the urine. Approximately 10% of a single dose of Phenylbutazone is excreted in bile as metabolites. About 60% of the urinary metabolites have been identified. A novel type of drug metabolite in man, the C-glucuronide, is formed by direct coupling of the pyrazolidine ring of Phenylbutazone to glucuronic acid via a C-C bond. Phenylbutazone is oxidised in a phenyl ring or in the side chain to hydroxylated metabolites, which may undergo subsequent O-glucuronidation. After a single dose, C-glucuronidation seems to be the dominant reaction, while oxidation becomes increasingly important after repeated administration. Due to different pharmacokinetic properties of the metabolites, the C-glucuronides are detected in highest concentrations in the urine, while the pharmacologically active compounds oxyphenbutazone and y-hydroxyphenbutazone predominate in plasma.

The biological (elimination) half-life of Phenylbutazone in man is long, with a mean of about 70 hours, and exhibits large interindividual and intraindividual variation. The interindividual variation is largely due to genetic factors. The intraindividual variation is dose and time dependent. In an individual there may be several critical dose levels where a change in the elimination kinetics takes place.

Since there is no correlation between the plasma level and the clinical or toxic effects of Phenylbutazone, there is at present no need for routine monitoring of plasma concentrations of the drug.


Clinical Pharmacokinetic Phenylbutazone Oxyphenbutazone Chronic Hepatic Disease Butazone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aarbakke, J.; Bending, M.R. and Davies, D.S.: Increased oxidation of Phenylbutazone during hydrocortisone infusion in man. British Journal of Clinical Pharmacology 4: 621–622 (1977a).PubMedCrossRefGoogle Scholar
  2. Aarbakke, J.; Bakke, O.M.; Milde, E.J. and Davies, D.S.: Disposition and oxidative metabolism of Phenylbutazone in Man. European Journal of Clinical Pharmacology 11: 359–366 (1977b).PubMedCrossRefGoogle Scholar
  3. Aggeler, P.M.; O’Reilly, R.A.; Leong, L. and Kowitz, P.E.: Potentiation of anticoagulant effect of warfarin by Phenylbutazone. New England Journal of Medicine 276: 496–502 (1967).PubMedCrossRefGoogle Scholar
  4. Alyares, A.P.; Kapelner, S.; Sassa, S. and Kappas, A.: Drug metabolism in normal children, lead-poisoned children, and normal adults. Clinical Pharmacology and Therapeutics 18: 179–183 (1975).Google Scholar
  5. Andreasen, F.: Protein binding of drugs in plasma from patients with acute renal failure. Acta Pharmacologica et Toxicologica 32: 417–429 (1973).PubMedCrossRefGoogle Scholar
  6. Awang, D.C.; Vincent, A. and Matsui, F.: Pattern of Phenylbutazone degradation. Journal of Pharmaceutical Sciences 62: 1673–1676 (1973).PubMedCrossRefGoogle Scholar
  7. Bakke, O.M.; Draffan G.H. and Davies, D.S.: The metabolism of Phenylbutazone in the rat. Xenobiotica 4: 237–254 (1974).PubMedCrossRefGoogle Scholar
  8. Bellward, G.D.;, Morgan, R.G.; Beauline, V.H. and Mitchell, A.G.: Effect of Phenylbutazone breakdown products on drug metabolism assay. Journal of Pharmacy and Pharmacology 24: 338–339 (1972).PubMedCrossRefGoogle Scholar
  9. Belpaire, F.M.; Bogaert, M.G. and Mussche, M.M.: Influence of acute renal failure on the protein binding of drugs in animals and in man. European Journal of Clinical Pharmacology 11: 27–32 (1977).PubMedCrossRefGoogle Scholar
  10. Blaschke, T.F.: Protein binding and kinetics of drugs in liver diseases. Clinical Pharmacokinetics 2: 32–44 (1977).PubMedCrossRefGoogle Scholar
  11. Boobis, S. and Brodie, M.J.: The effects of chronic alcohol ingestion and alcoholic liver disease on drug-protein binding. British Journal of Clinical Pharmacology 4: 629 (1977).CrossRefGoogle Scholar
  12. Brodie, B.B. and Hogben, C.A.M.: Some physicochemical factors in drug action. Journal of Pharmacy and Pharmacology 9: 345–380 (1957).PubMedCrossRefGoogle Scholar
  13. Brodie, B.B.; Lowman, E.W.; Burns, J.J.; Lee, P.R.; Chenkin, T.; Goldman, A.; Weiner, M. and Steele, M.J.: Observations on the antirheumatic and physiologic effects of Phenylbutazone (Butazolidin) and some comparisons with cortisone. American Journal of Medicine 16: 181–190 (1954).PubMedCrossRefGoogle Scholar
  14. Brooks, P.M.; Walker, J.J.; Dick, W.C.; Anderson, J.A. and Fowler, P.D.: Phenylbutazone: A clinico-pharmacological study in rheumatoid arthritis. British Journal of Clinical Pharmacology 2: 437–442 (1975).PubMedCrossRefGoogle Scholar
  15. Bruck, E.; Fearnley, M.E.; Meanock, I. and Patley, H.: Phenylbutazone therapy, relation between the toxic and therapeutic effects and the blood level. Lancet 1: 225–228 (1954).CrossRefGoogle Scholar
  16. Burns, J.J.; Rose, R.K.; Chenkin, T.; Goldman, A.; Schulert, A. and Brodie, B.: The physiological disposition of Phenylbutazone (Butazolidin) in man and a method for its estimation in biological material. Journal of Pharmacology and Experimental Therapeutics 109: 346–357 (1953).PubMedGoogle Scholar
  17. Burns, J.J.; Rose, R.K.; Goodwin, S.; Reichenthal, J.; Horning, E.C. and Brodie, B.B.: The metabolic fate of Phenylbutazone (Butazolidin) in man. Journal of Pharmacology and Experimental Therapeutics 11 3: 481–489 (1955).Google Scholar
  18. Chen, W.; Vrindten, P.A.; Dayton, P.G. and Burns, J.J.: Accelerated aminopyrine metabolism in human subjects pretreated with Phenylbutazone. Life Sciences 1: 35–42 (1962).CrossRefGoogle Scholar
  19. Christensen, L.K.; Hansen, J.M. and Kristensen, M.: Sulphaphenazole-induced hypoglycacmic attacks in tolbutamide-treated diabetics. Lancet 2: 1298–1301 (1963).PubMedCrossRefGoogle Scholar
  20. Cunningham, J.L.; Leyland, M.J.; Delamore, I.W. and Price Evans, D.A.: Acetanilide oxidation in phenylbutazone-associated hypoplastic anaemia. British Medical Journal 3: 313–317 (1974).PubMedCrossRefGoogle Scholar
  21. Davies, D.S. and Thorgeirsson, S.S.: Mechanism of hepatic drug oxidation and its relationship to individual differences in rates of oxidation in man. Annals of New York Academy of Sciences 179: 411–420 (1971).CrossRefGoogle Scholar
  22. Dayton, P.G.; Israili, Z.H. and Perel, J.M.: Influence of binding on drug metabolism and distribution. Annals of New York Academy of Sciences 226: 172–194 (1973).CrossRefGoogle Scholar
  23. Dewse, C.D.: Inhibition of DNA synthesis in cultured human lymphocytes by Phenylbutazone and oxyphenbutazone. Journal of Pharmacy and Pharmacology 28: 596–598 (1976).PubMedCrossRefGoogle Scholar
  24. Dewse, C.D. and Potter, C.G.: Inhibitory effect of Phenylbutazone and oxyphenbutazone on DNA synthesis in normal human bone marrow cells in vitro. Journal of Pharmacy and Pharmacology 27: 523–526 (1975).PubMedCrossRefGoogle Scholar
  25. Dieterle, W.; Faigle, J.W.; Früh, F.; Mory, H.; Theobald, W.; Alt, K.O. and Richter, W.J.: Metabolism of Phenylbutazone in man. Arzneimittel Forschung 26: 572–577 (1976).PubMedGoogle Scholar
  26. Dieterle, W.; Faigle, J.W.; Mory, H.; Richter, W.J. and Theobald, W.: Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan) in man. European Journal of Clinical Pharmacology 9: 135–145 (1975).PubMedCrossRefGoogle Scholar
  27. Faigle, J.W. and Dieterle, W.: The biotransformation of Phenylbutazone (Butazolidin). Journal of International Medical Research 5 (Suppl. 2): 2–14 (1977).PubMedGoogle Scholar
  28. Farr, M. and Willis, J.V.: Investigation of Phenylbutazone in synovial fluid. Journal of International Medical Research 5: 26–29 (1977).PubMedGoogle Scholar
  29. Field, J.B.; Ohta, M.; Boyle, C. and Remer, A.: Potentiation of acetohexamide hypoglycemia by Phenylbutazone. New England Journal of Medicine 277: 889–899 (1967).PubMedCrossRefGoogle Scholar
  30. Fuchs, W.: Blutspiegelbestimmung von Butazolidin und Tanderil. Münchener Medizinische Wochenschrift 107: 1267–1270 (1965).PubMedGoogle Scholar
  31. Hansen, J.M. and Christensen, L.K.: Drug interactions with oral sulphonylurea hypoglycaemic drugs. Drugs 13: 24–34 (1977).PubMedCrossRefGoogle Scholar
  32. Herrmann, B.: Uber den Stoffwechsel des Butazolidin. Medicina Experimentalis 4: 170–178 (1960).Google Scholar
  33. Hansen, E.C. and Nielsen, E.; Fenylbutazonkoncentrationen i blodet ved anvendelse af Butazolidin-salve. Ugeskrift for Laeger. 131: 208–210 (1972).Google Scholar
  34. Horwitz, D.; Thorgeirsson, S.S. and Mitchell, J.R.: The influence of allopurinol and size of dose on the metabolism of Phenylbutazone in patients with gout. European Journal of Clinical Pharmacology 12: 133–136 (1977).PubMedCrossRefGoogle Scholar
  35. Hvidberg, E.F.; Andreasen, P.B. and Ranek, L.: Plasma half-life of Phenylbutazone in patients with impaired liver function. Clinical Pharmacology and Therapeutics 15: 171–177 (1974).PubMedGoogle Scholar
  36. Inman, W.H.W.: Study of fatal bone marrow depression with special reference to Phenylbutazone and oxyphenbutazone. British Medical Journal 1: 1500–1505 (1977).PubMedCrossRefGoogle Scholar
  37. Jahnchen, E. and Levy, G.: Determination of Phenylbutazone in plasma. Clinical Chemistry 18: 984–986 (1972).PubMedGoogle Scholar
  38. Kellermann, G.; Luyten-Kellermann, M.; Horning, M.G. and Stafford, M.: Correlation of aryl hydrocarbon hydroxylase activity of human lymphocyte cultures and plasma elimination rates for antipyrine and Phenylbutazone. Drug Metabolism and Disposition 3: 47–50 (1975).PubMedGoogle Scholar
  39. Koch-Weser, J. and Sellers, E.M.: Drug interactions with coumarin anticoagulants. New England Journal of Medicine 285: 487–498; 547-558 (1971).CrossRefGoogle Scholar
  40. Kristensen, M.: Medikament-Medikamentinteraktion. Thesis (Danske laegestudeurendes forlag, Copenhagen 1973).Google Scholar
  41. Leber, H.W.; Harders, A. and Schütterle, G.: Untersuchungen zum Einfluss der Urämie auf die Metabolisierung von Phenylbutazon und Aminophenazon beim Menschen. Klinische Wochenschrift 50: 1092–1096 (1972).PubMedCrossRefGoogle Scholar
  42. Levi, A.J.; Sherlock, S. and Walker, D.: Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet 1: 1275–1279 (1968).PubMedCrossRefGoogle Scholar
  43. Lewis, R.J.; Trager, W.F.; Chan, K.K.; Breckenridge, A.; Orme, M.; Rowland, M. and Schary, W.; Warfarin. Stereochemical aspects of its metabolism and the interaction with Phenylbutazone. Journal of Clinical Investigation 53: 1607–1617 (1974).PubMedCrossRefGoogle Scholar
  44. Lukas, G.; Maggio-Cavaliere, M.B.; Borman, C.B. and Arnold, J.D.: Relationships between dose and bioavailability of Phenylbutazone. Journal of Clinical Pharmacology 14: 397–398 (1974).Google Scholar
  45. MacLeod, S.M. and Sellers, E.M.: Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants. Drugs 11: 461–470 (1976).PubMedCrossRefGoogle Scholar
  46. McGilveray, I.J.; Midha, K.K.; Brien, R. and Wilson, L.: The assay of Phenylbutazone in human plasma by a specific and sensitive gas-liquid Chromatographic procedure. Journal of Chromatography 89: 17–22 (1974).PubMedCrossRefGoogle Scholar
  47. Mussche, M.M.; Belpaire, F.M. and Bogaert, M.G.; Plasma protein binding of Phenylbutazone during recovery from acute renal failure. Eur. J. Clin. Pharmacol. 9: 69–71 (1975).PubMedCrossRefGoogle Scholar
  48. O’Malley, I.; Crooks, J.; Duke, E. and Stevenson, I.H.: Effect of age and sex on human drug metabolism. British Medical Journal 3: 607–609 (1971).PubMedCrossRefGoogle Scholar
  49. Orme, M.; Holt, P.J.L.; Hughes, G.R.V.; Bulpitt, C.J.; Draffan, G.H.; Thorgeirsson, S.S.; Williams, F. and Davies, D.S.: Plasma concentration of Phenylbutazone and its therapeutic effect — Studies in patients with rheumatoid arthritis. British Journal of Clinical Pharmacology 3: 185–191 (1976).PubMedCrossRefGoogle Scholar
  50. Perel, J.M.; Snell, M.McM.; Chen, W. and Dayton, P.G.: A study of structure-activity relationships in regard to species difference in the Phenylbutazone series. Biochemical pharmacology 13: 1305–1317 (1964).PubMedCrossRefGoogle Scholar
  51. Pond, S.M.; Birkett, D.J. and Wade, D.N.: Mechanisms of inhibition of tolbutamide metabolism: Phenylbutazone, oxyphenbutazone, sulfaphenazole. Clinical Pharmacology and Therapeutics 22: 573–579 (1978).Google Scholar
  52. Pound, N.J.; McGilveray, I.J. and Sears, R.W.: Analysis of Phenylbutazone in plasma by high-speed liquid chromatography. Journal of Chromatography 89: 23–30 (1974).PubMedCrossRefGoogle Scholar
  53. Pulver, R.; Ueber Irgapyrin, ein neues Autirheumaticum und Analgeticum. Schweizerische Medizinische Wochenschrift 12: 308–310 (1950).Google Scholar
  54. Richter, W.J.; Alt, K.O.; Dieterle, W.; Faigle, J.W.; Kriemler, H.P.; Mory, H. and Winkler, T.: C-Glucuronides, a novel type of drug metabolite. Helvetica Chimica Acta 58: 2512–2517 (1975).PubMedCrossRefGoogle Scholar
  55. Schmid, R.W.: Uber das hydrolysegleichgewicht von Phenylbutazon (Butazolidin). Helvetica Chimica Acta 53: 2239–2251 (1970).PubMedCrossRefGoogle Scholar
  56. Schulz, E. and Schmidt, F.H.; Uber den einfluss von Sulfaphenazol. Phenylbutazon und Phenprocoumarol auf die Elimination von Glibenclamid beim Menschen. Verhandlungen Deutsche Gesellschaft fur Innere Medizin 76: 435–438 (1970).Google Scholar
  57. Smith, C.S.; Chinn, S. and Watts, R.W.E.: The sensitivity of human bone marrow granulocyte/monocyte precursor cells to Phenylbutazone, oxyphenbutazone and gamma-hydroxyphenbutazone in vitro, with observations on the bone marrow colony formation in phenylbutazone-induced granulocytopoenia. Biochemical Pharmacology 26: 847–852 (1977).PubMedCrossRefGoogle Scholar
  58. Sioufi, A.; Caudal, F. and Marfil, F.: GLC determination of Phenylbutazone in human plasma. Journal of Pharmaceutical Sciences 67: 243–245 (1978).PubMedCrossRefGoogle Scholar
  59. Tanimura, Y.; Saitoh, Y.; Nakagawa, F. and Suzuki, T.: Determination of Phenylbutazone and its metabolites in plasma by gas-liquid Chromatographic procedure. Chemical and Pharmaceutical Bulletin 23: 651–658 (1975).CrossRefGoogle Scholar
  60. Triggs, E.J.; Nation, R.L.; Long, A. and Ashley, J.J.: Pharmacokinetics in the elderly. European Journal of Clinical Pharmacology 8: 55–62 (1975).PubMedCrossRefGoogle Scholar
  61. Vesell, E.S. and Page, J.G.: Genetic control of drug levels in man: Phenylbutazone. Science 159: 1479–1480 (1968).PubMedCrossRefGoogle Scholar
  62. Wagner, J., Stierlin, H. and Pulver, R.: Metabolism of oxyphenbutazone. Abstracts VII. European Rheumatology Congress, Brighton. England (1971).Google Scholar
  63. Wallace, J.E.: Ultraviolet spectrophotometric determination of Phenylbutazone in biologic specimens. Journal of Pharmaceutical Sciences 57: 2053–2056 (1968).PubMedCrossRefGoogle Scholar
  64. Wallace, S. and Brodie, M.J.: Decreased drug binding in serum from patients with chronic hepatic disease. European Journal of Clinical Pharmacology 9: 429–432 (1976).CrossRefGoogle Scholar
  65. Weiner, M.; Chenkin, T. and Burns, J.J.: Observations on the metabolic transformation and effects of Phenylbutazone in subjects with hepatic disease. American Journal of the Medical Sciences 228: 36–39 (1954).PubMedCrossRefGoogle Scholar
  66. Weinkam, R.J.; Rowland, M. and Meffin, P.J.: Determination of Phenylbutazone, tolbutamide and metabolites in plasma and urine using chemical ionization mass spectrometry. Biomedical Mass Spectrometry 4: 42–47 (1977).PubMedCrossRefGoogle Scholar
  67. Whittaker, J.A. and Price Evans, D.A.: Genetic control of Phenylbutazone metabolism in man. British Medical Journal 4: 323–328 (1970).PubMedCrossRefGoogle Scholar
  68. Yacobi, A. and Levy, G.: Importance of assay specificity for plasma protein binding determinations. Journal of Pharmacokinetics and Biopharmaceutics 3: 439–441 (1975).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • Jarle Aarbakke
    • 1
  1. 1.Institute of Medical BiologyUniversity of TromsøTromsøNorway

Personalised recommendations