Clinical Investigation

Kidney International (1979) 16, 187–195; doi:10.1038/ki.1979.120

Pharmacodynamic analysis of the furosemide-probenecid interaction in man

Polavat Chennavasin1, Ruth Seiwell1, D Craig Brater1 and Winnie M M Liang1

1Department of Pharmacology, Division of Clinical Pharmacology, The University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas

Correspondence: Dr D Craig Brater, The University of Texas Health Science Center at Dallas, Southwestern Medical School, Department of Pharmacology, Division of Clinical Pharmacology, 5323 Harry Hines Boulevard, Dallas, Texas 75235, USA

Received 18 December 1978; Revised 26 February 1979.

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Abstract

Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Probenecid pretreatment in man increased the overall response to furosemide in contrast to animal studies in which probenecid decreased response by inhibiting proximal renal tubular secretion of furosemide to its active site. We administered i.v. 40 mg of furosemide to eight normal volunteers with and without probenecid pretreatment and measured serum and urinary furosemide concentrations by high performance liquid chromatography to determine the mechanism of probenecid's effect. Probenecid pretreatment significantly increased serum furosemide concentration. Urinary furosemide excretion rate paralleled urinary sodium excretion rate; both were initially decreased but were later increased by probenecid pretreatment. Probenecid pretreatment decreased renal and nonrenal clearance of furosemide (1.04 plusminus 0.31 vs. 0.29 plusminus 0.06 ml/kg/min, P < 0.05; and 1.00 plusminus 0.18 vs. 0.27 plusminus 0.03 ml/kg/min, P < 0.004, respectively). Although probenecid inhibited renal clearance for the duration of the study, accumulation of furosemide in serum from concomitant effects on nonrenal clearance allowed more furosemide to appear in the urine at later times, increasing response. This analysis demonstrated the importance of probenecid's effects on nonrenal elimination of furosemide in determining the overall response to furosemide. The relationship between furosemide concentrations and response depicted a sigmoid dose-response curve. Probenecid shifted the serum dose-response relationship to the right but did not affect the relationship between urinary furosemide excretion rate and response, demonstrating the importance of the urinary (as opposed to serum) concentration-response relationship of furosemide in normal man. This relationship will provide a valuable tool for assessing response to diuretics in various disease states where resistance to diuretics occurs.

Analyse pharmacodynamique de l'interaction furosémide-probénécide chez l'homme. Le pré-traitement par le probénécide chez l'homme augmente la réponse globale au furosémide par opposition aux études chez l'animal où le probénécide diminue cette réponse en inhibant la sécrétion tubulaire proximale de furosémide. Nous avons administré i.v. 40 mg de furosémide par voie à huit volontaires normaux, avec ou sans pré-traitement par le probénécide, et mesuré les concentrations de furosémide sériques et urinaires par chromatographie liquide à haute résolution afin d'étudier le mécanisme de l'effet du probénécide. Le pré-traitement par le probénécide augmente significativement la concentration sérique de furosémide. L'excrétion urinaire de furosémide est parallèle à l'excrétion urinaire de sodium. Ces deux dernières sont initialement diminuées mais ultérieurement augmentées par le pré-traitement au moyen de probénécide. Le pré-traitement par le probénécide diminue les clearances rénale et non-rénale du furosémide (1,04 plusminus 0,31 vs. 0,29 plusminus 0,06 ml/kg/min, P < 0,05; et 1,00 plusminus 0,18 vs. 0,27 plusminus 0,03 ml/kg/min, P < 0,004, respectivement). Bien que le probénécide diminue la clearance rénale pendant la durée de l'étude, l'accumulation sérique de furosémide due aux effets sur la clearance non rénale permet l'apparition dans l'urine de quantités plus importantes à des temps ultérieurs, ce qui augmente la réponse. Cette analyse démontre l'importance des effets du probénécide sur l'élimination non rénale de furosémide dans le déterminisme de la réponse globale au furosémide. La relation entre les concentrations de furosémide et la réponse décrit une courbe dose-réponse sigmoïde. Le probénécide déplace la courbe dose-réponse sérique vers la droite mais n'affecte pas la relation entre l'excrétion urinaire de furosémide et la réponse, ce qui démontre l'importance de la relation entre la concentration urinaire (à la différence de la concentration sérique) et la réponse. Cette relaition fournit un instrument utile pour évaluer la réponse aux diurétiques dans divers états où la résistance à ces drogues est observée.

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References

  1. Stason WB, Cannon PJ, Heinemann HO, Laragh JH: Furosemide: A clinical evaluation of its diuretic action. Circulation 34:910–920, 1966
  2. Kirkendall WM, Stein JH: Clinical pharmacology of furosemide and ethacrynic acid. Am J Cardiol 22:162–167, 1968
  3. Greenblatt DJ, Duhme DW, Allen MD, Kock-Weser J: Clinical toxicity of furosemide in hospitalized patients. Am Heart J 94:6–13, 1977
  4. Rupp W: Pharmacokinetics and pharmacodynamics of lasix. Scot Med J 19:5–13, 1974
  5. Cutler RE, Forrey AW, Christopher TG, Kimpel BM: Pharmacokinetics of furosemide in normal subjects and functionally anephric patients. Clin Pharmacol Ther 15:588–596, 1974
  6. Branch RA, Roberts CJC, Homeida M, Levine D: Determinants of response to frusemide in normal subjects. Br J Clin Pharmacol 4:121–127, 1977
  7. Homeida M, Roberts C, Branch RA: Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man. Clin Pharmacol Ther 22:402–409, 1977 | PubMed | ChemPort |
  8. Burg MB: Tubular chloride transport and the mode of action of some diuretics. Kidney Int 9:189–197, 1976 | PubMed | ChemPort |
  9. Jacobson HR, Kokko JP: Diuretics: Sites and mechanism of action. Annu Rev Pharmacol Toxicol 16:201–214, 1976
  10. Seely JF, Dirks JH: Site of action of diuretic drugs. Kidney Int 11:1–8, 1977
  11. Burg M, Stoner L, Cardinal J, Green N: Furosemide effect on isolated perfused tubules. Am J Physiol 225:119–124, 1973 | PubMed | ISI | ChemPort |
  12. Bowman RH: Renal secretion of [35S] furosemide and its depression by albumin binding. Am J Physiol 229:93–98, 1975
  13. Rane A, Villeneuve JP, Stone WJ, Nies AS, Wilkinson GR, Branch RA: Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia. Clin Pharmacol Ther 24:199–207, 1978
  14. Deetjen P: Micropuncture studies on site and mode of diuretic action of furosemide. Ann NY Acad Sci 139:408–415, 1966
  15. Hirsch GH, Pakuts AP, Bayne AJ: Furosemide accumulation by renal tissue. Biochem Pharmacol 24:1943–1946, 1975
  16. Hook JB, Williamson HE: Influence of probenecid and alterations in acid-base balance of the saluretic activity of furosemide. J Pharmacol Exp Ther 149:404–408, 1965
  17. Brater DC: Effects of probenecid on furosemide response. Clin Pharmacol Ther 24:548–554, 1978
  18. Metzler CM, Elfring GL, McEwen AJ: A Users Manual for Nonlin and Associated Programs. Upjohn Company, Kalamazoo, Michigan, 1974
  19. Neter J, Wasserman W: Applied Linear Statistical Models. Homewood, Ill., Richard D. Irwin, Inc., 1974
  20. Wagner JG: Biopharmaceutics and Relevant Pharmacokinetic. Hamilton, Illinois, Drug Intelligence Publications, 1971, pp. 247–248
  21. Yonden WJ: Statistical Methods for Chemists. John Wiley & Sons, Inc., 1951, p. 44
  22. Honari J, Blair AD, Cutler RE: Effects of probenecid on furosemide kinetics and natriuresis in man. Clin Pharmacol Ther 22:395–401, 1977 | PubMed | ChemPort |
  23. Prandota J, Pruitt AW: Furosemide binding to human albumin and plasma of nephrotic children. Clin Pharmacol Ther 17:159–166, 1974
  24. Beyer KH, Baer JE: The site and mode of action of some sulfonamide-derived diuretics. Med Clin North Am 59:735–750, 1975
  25. Burg M, Green N: Effect of ethacrynic acid on the thick ascending limb of Henle's loop. Kidney Int 4:301–308, 1973
  26. Baer JE, Leidy HL, Brooks AV, Beyer KH: The physiological disposition of chlorothiazide (Diuril) in the dog. J Pharmacol Exp Ther 125:295–302, 1959
  27. Beyer KH: The mechanism of action of chlorothiazide. Ann NY Acad Sci 71:363–379, 1958
  28. Beyer KH, Baer JE: Physiological basis for the action of newer diuretic agents. Pharmacol Rev 13:517–562, 1961 | PubMed | ISI | ChemPort |
  29. Friedman PA, Roch-Ramel F: Hemodynamic and natriuretic effects of bumetanide and furosemide in the cat. J Pharmacol Exp Ther 203:82–91, 1977
  30. Weiner IM, Washington JA ii, Mudge GH: On the mechanism of action of probenecid on renal tubular secretion. Johns Hopkins Med J 106:333–346, 1960
  31. Murphy J, Casey W, Lasagna L: The effect of dosage regimen on the diuretic efficacy of chlorothiazide in human subjects. J Pharmacol Exp Ther 134:286–291, 1961
  32. Brater DC: Increase in diuretic effect of chlorothiazide by probenecid. Clin Pharmacol Ther 23:259–265, 1978
  33. Beyer KH, Russo HF, Tillson EK, Miller AK, Verwey WF, Gass SR: "Benemid", p-(di-n-Propylsulfamyl)-benzoic acid: Its renal affinity and its elimination. Am J Physiol 166:625–639, 1951 | PubMed | ChemPort |
  34. Dayton PG, Yu TF, Chen W, Berger L, West LA, Gutman AB: The physiological disposition of probenecid, including renal clearance, in man, studies by an improved method for its estimation in biological material. J Pharmacol Exp Ther 140:278–286, 1963 | PubMed | ISI | ChemPort |
  35. Rose HJ, Pruitt AW, McNay JL: Effect of experimental azotemia on renal clearance of furosemide in the dog. J Pharmacol Exp Ther 196:238–247, 1976
  36. Rose HJ, Pruitt AW, Dayton PT, McNay JL: Relationship of urinary furosemide excretion rate to natriuretic effect in experimental azotemia. J Pharmacol Exp Ther 199:490–497, 1976
  37. Lawrence JR, Ansari AF, Elliott HL, Sumner DJ, Phil D, Brunton GF, Whiting B, Whitesmith R: Kinetic and dynamic comparison of piretanide and furosemide. Clin Pharmacol Ther 23:558–564, 1977
  38. Kelly MR, Cutler RE, Forrey AW, Kimpel BM: Pharmacokinetics of orally administered furosemide. Clin Pharmacol Ther 15:178–185, 1973

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