The clinical investigator

, Volume 72, Issue 12, pp 1071–1075 | Cite as

Interaction of allopurinol and hydrochlorothiazide during prolonged oral administration of both drugs in normal subjects

I. Uric acid kinetics
  • W. Löffler
  • R. Landthaler
  • J. X. de Vries
  • I. Walter-Sack
  • A. Ittensohn
  • A. Voss
  • N. Zöllner
Clinical Pharmacology


The interaction of allopurinol (300 mg/day) and hydrochlorothiazide (50 mg/day) was studied in seven healthy male volunteers during prolonged coadministration of the two drugs using defined dietary conditions. A formula diet was administered with the allopurinol throughout the 24-day study, while hydrochlorothiazide was added during days 11–21. After the addition of hydrochlorothiazide both plasma uric acid and plasma oxipurinol rose for 6 days – 24% and 30%, respectively, compared to steady-state levels during allopurinol alone (P < 0.01 each). In neither substance were variations in renal excretion significant. By the end of combined treatment (day 21), the changes induced by hydrochlorothiazide had already been reversed to a considerable extent. It is concluded that both in normal individuals and in patients with normal renal clearance of uric acid the effect of hydrochlorothiazide on the plasma concentration and renal excretion of oxipurinol is small. When taking both drugs, there is no increased risk during long-term treatment, and a risk is even questionable during the first days.

Key words

Allopurinol Oxipurinol Hydrochlorothiazide Uric acid Drug interaction 





uric acid






allopurinol hypersensitivity syndrome


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  1. 1.
    Cameron JS, Simmonds HA (1987) Use and abuse of allopurinol. Br Med J, pp 1504–1505Google Scholar
  2. 2.
    Casas E, Puig JG, Mateos FA, Jimenez ML, Michan AD, Ramos TH (1990) The allopurinol hyersensitivity syndrome: Its relation to plasma oxypurinol levels. Adv Exp Med Biol 253A:257–260Google Scholar
  3. 3.
    Day RO, Miners J, Birkett DJ, Graham GG, Whitehead A (1988) Relationship between plasma oxipurinol concentrations and xanthine oxidase activity in volunteers dosed with allopurinol. Br J Clin Pharmacol 26:429–434Google Scholar
  4. 4.
    Demanet JC, Paduart P, Fichefet JP, Delcroix C (1970) Tolerance and ionic effects in aldosterone antagonist (amiloride) as compared with a thiazide. J Clin Pharmacol 30:269–273Google Scholar
  5. 5.
    De Vries JX, Voss A, Kutschker C, Reiter S (1993) The simultaneous determination of allopurinol and oxipurinol in human plasma and urine by high-performance liquid chromatography. Arzneimittelforschung 43:1072–1075Google Scholar
  6. 6.
    Edwards NL, Recker D, Airozo D, Fox IH (1981) Enhanced purine salvage during allopurinol therapy: an important pharmacologic property in humans. J Lab Clin Med 98:673–683Google Scholar
  7. 7.
    Elion GB (1978) Allopurinol and other inhibitors of urate synthesis. In: Kelley WN, Weiner IM (eds) Uric acid, handbook of experimental pharmacology, vol 51. Springer, Berlin Heidelberg New York, pp 485–514Google Scholar
  8. 8.
    Elion GB, Kovensky A, Hitchings GH, Metz E, Rundles RW (1966) Metabolic studies of allopurinol, an inhibitor of xanthine oxidase. Biochem Pharmacol 15:863–880Google Scholar
  9. 9.
    Elion GB, Yu TF, Gutman AB, Hitchings GH (1968) Renal clearance of oxipurinol, the chief metabolite of allopurinol. Am J Med 45:69–77Google Scholar
  10. 10.
    Hande KR (1986) Evaluation of a thiazide-allopurinol drug interaction. Am J Med Sci 292:213–216Google Scholar
  11. 11.
    Hande K, Reed E, Chabner B (1978) Allopurinol kinetics. Clin Pharmacol Ther 23:598–605Google Scholar
  12. 12.
    Hande KR, Noone RM, Stone WJ (1984) Severe allopurinol toxicity; description and guidelines for prevention in patients with renal insufficiency. Am J Med 76:47–56Google Scholar
  13. 13.
    Helgeland A, Hjermann I, Holme I, Leren P (1978) Serum triglycerides and serum uric acid in untreated patients with mild hypdertension. Am J Med 64:34–38Google Scholar
  14. 14.
    Kelley WN, Greene ML, Fox IH, Rosenbloom FM, Levy RI, Seegmiller JE (1970) Effects of orotic acid on purine and lipoprotein metabolism in man. Metabolism 19:1025–1035Google Scholar
  15. 15.
    Löffler W, Gröbner W (1988) A study of dose-response relationship of allopurinol in the presence of low or high purine turnover. Klin Wochenschr 66:153–159Google Scholar
  16. 16.
    Maschio G, Tessitore N, et al (1981) Prevention of calcium nephrolithiasis with low-dose thiazide, amiloride and allopurinol. Am J Med 71:623–626Google Scholar
  17. 17.
    May P, Pilorz H, Duhme C, Pöpperl H, Braun J (1984) Harnsteinprohylaxe mit Thiaziden und Allopurinol. Urologe A 23:87–90Google Scholar
  18. 18.
    McInnes GT, Lawson DH, Jick H (1981) Acute adverse reactions attributed to allopurinol in hospitalised patients. Ann Rheum Dis 40:245–249Google Scholar
  19. 19.
    Mertz DP, Eichhorn R (1984) Does benzbromarone in therapeutic doses raise renal excretion of oxipurinol? Klin Wochenschr 62:1170–1172Google Scholar
  20. 20.
    Nemati M, Kyle MC, Freis ED (1977) Clinical study of ticrynafen. JAMA 237:652–657Google Scholar
  21. 21.
    Nicotero JA, Scheib ET, Martinez R, Rodnan GP, Shapiro AP (1970) Prevention of hyperuricemia by allopurinol in hypertensive patients treated with chlorothiazide. New Engl J Med 282:133–135Google Scholar
  22. 22.
    Peterson GM, Boyle RR, Francis HW, Oliver NWJ, Paterson J, Von Witt RJ, Taylor GR (1990) Dosage prescribing and plasma oxipurinol levels in patients receiving allopurinol therapy. Eur J Clin Pharmacol 39:419–421Google Scholar
  23. 23.
    Ponticelli C, Lechi A, DiPerri T, Redaelli B, Locatelli F, Rivolta E, Covi G, Messa GL, Pincella G, Pedrini L, Recchia M, Gouere P (1979) Multicentre comparative trial of tienilic tienilic acid and hydrochlorothiazide in hyertensive patients. Eur J Clin Pharmacol 16:319–322Google Scholar
  24. 24.
    Reese O, Steele T (1976) Renal transport of urate during diuretic-induced hypouricemia. Am J Med 60:973–979Google Scholar
  25. 25.
    Roos JC, Boer P, Peuker KH, Dorhout Mees EJ (1982) Changes in intrarenal uric acid handling during chronic spironolactone treatment in patients with essential hypertension. Nephron 32:209–213Google Scholar
  26. 26.
    Simmonds HA, Cameron JS, Morris GS, Davies PM (1986) Allopurinol in renal failure and the tumor lysis syndrome. Clin Chim Acta 160:189–195Google Scholar
  27. 27.
    Singer JZ, Wallace SL (1986) The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum 29:82–87Google Scholar
  28. 28.
    Steele TH, Oppenheimer S (1969) Factors affecting urate excretion following diuretic administation in man. Am J Med 47:564–574Google Scholar
  29. 29.
    Waal-Manning H, Simpson FO (1979) One year follow-up of hypertensive patients treated with tienilic acid or a diuretic with or without uric acid-lowering drugs. Clin Sci 57:379s-382sGoogle Scholar
  30. 30.
    Walter-Sack I, Gröbner W, Zöllner N (1979) Verlauf der Oxipurinol-Spiegel im Plasma nach akuter und chronischer Gabe von Allopurinol in verschiedenen galenischen Zubereitungen. Arzneimittelforschung 29:839–842Google Scholar
  31. 31.
    Walter-Sack I, Wolfram G, Zöllner N (1987) Alternation of oral carbohydrate tolerance during administration of a fiber-free formula diet. Klin Wochenschr 65:121–128Google Scholar
  32. 32.
    Wood MH, O'Sullivan WJ, Wilson M, Tiller DJ (1974) Potentation of an effect of allopurinol on pyrimidine metabolism by chlorothiazide in man. Clin Exp Pharmacol Physiol 1:53–58Google Scholar
  33. 33.
    Yü TF, Berger L, Sarkozi L, Kaung C (1981) Effects of diuretics on urate and calcium excretion. Arch Intern Med 141:915–919Google Scholar
  34. 34.
    Zöllner N (1963) Eine einfache Modifikation der enzymatischen Harnsäurebestimmung. Z Klin Chem 1:178–182Google Scholar
  35. 35.
    Zöllner N, Griebsch A, Gröbner W (1972) Einflu\ verschiedener Nahrungspurine auf den Harnsäurestoffwechsel. Ernährungsumschau 3:79–82Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • W. Löffler
    • 1
  • R. Landthaler
    • 1
  • J. X. de Vries
    • 2
  • I. Walter-Sack
    • 2
  • A. Ittensohn
    • 2
  • A. Voss
    • 2
  • N. Zöllner
    • 1
  1. 1.Medizinische PoliklinikUniversität MünchenMünchenGermany
  2. 2.Abteilung Klinische Pharmakologie, Medizinische KlinikUniversität HeidelbergHeidelbergGermany

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