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Renal transport kinetics of furosemide in the isolated perfused rat kidney


Direct quantitative data and corresponding theory are provided for the effect of protein binding on the renal transport of furosemide. Drug studies were performed with various combinations of bovine serum albumin and dextran. This resulted in a percent unbound (fu) of furosemide ranging from 0.785 to 85.8%. The corrected renal (CLr/GFR) and secretion (CLs/GFR) clearances of furosemide were observed to increase with percent free, but in a nonproportional manner. Plots ofCLr/GFR orCLs/GFR vs.fu appeared to have a prominenty intercept as well as a convex ascending curve. In addition, the excretion ratio [ER=CLr/ (fu · GFR)] was reduced from 60.8 to 8.72 asfu increased. Overall, the data were best fitted to a model in which two Michaelis-Menten terms wre used to describe renal tubular transport, and secretion was dependent upon free drug concentrations in the perfusate. The results demonstrate that the renal mechanisms of furosemide excretion are more complex than previously reported and that active secretion may involve two different transport systems over the concentration range studied.

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  1. 1.

    R. H. Bowman. Renal secretion of35S-furosemide and its depression by albumin binding.Am. J. Physiol. 229:93–98 (1975).

  2. 2.

    S. Hall and M. Rowland. Influence of fraction unbound upon the renal clearance of furosemide in the isolated perfused rat kidney.J. Pharmacol. Exp. Ther. 232:263–268 (1985).

  3. 3.

    F. J. Koschier and M. Acara. Transport of 2,4,5-trichloroacetate in the isolated, perfused rat kidney.J. Pharmacol. Exp. Ther. 208:287–293 (1979).

  4. 4.

    G. Levy. Effect of plasma protein binding on renal clearance of drugs.J. Pharm. Sci. 69: 482–483 (1980).

  5. 5.

    S. Øie and L. Z. Benet. Altered drug disposition in disease states.Annu. Rep. Med. Chem.,15:277–287 (1980).

  6. 6.

    I. M. Weiner. Excretion of drugs by the kidney. In B. B. Brodie and J. R. Gillette (eds.),Handbook of Experimental Pharmacology, Vol. 28, Part 1, Springer, Berlin, 1971, pp. 328–353.

  7. 7.

    I. M. Weiner. Transport of weak acids and basis. In J. Orloff and R. W. Berliner (eds.),Handbook of Physiology, Section 8,Renal Physiology, American Physiological Society, Washington, D.C., 1973, pp. 521–554.

  8. 8.

    L. Z. Benet. Pharmacokinetics/pharmacodynamics of furosemide in man: A review.J. Pharmacokin. Biopharm. 7:1–27 (1979).

  9. 9.

    R. E. Cutler and A. D. Blair. Clinical pharmacokinetics of furosemide.Clin. Pharmacokinet. 4:279–296 (1979).

  10. 10.

    K. E. Kim, G. Onesti, J. H. Moyer, and C. Swartz. Ethacrynic acid and furosemide: Diuretic and hemodynamic effects and clinical uses.Am. J. Cardiol. 27:407–415 (1971).

  11. 11.

    W. M. Kirkendall and J. H. Stein. Clinical pharmacology of furosemide and ethacrynic acid. Am. J. Cardiol.22:162–167 (1968).

  12. 12.

    W. B. Stason, P. J. Cannon, H. O. Heinemann, and J. H. Laragh. Furosemide: A clinical evaluation of its diuretic action.Circulation 34:910–920 (1966).

  13. 13.

    P. Chennavasin, R. Seiwell, D. C. Brater, and W. M. M. Liang. Pharmacodynamic analysis of the furosemide-probenecid interaction in man.Kidney Int. 16:187–195 (1979).

  14. 14.

    T. P. Green and B. L. Mirkin. Resistance of proteinuric rats to furosemide: Urinary drug binding as a determinant of drug effect.Life Sci. 26:623–630 (1980).

  15. 15.

    D. E. Smith and L. Z. Benet. Relationship between urinary excretion rate, steady-state plasma levels and diuretic response of furosemide in the rat.Pharmacology 19:301–306 (1979).

  16. 16.

    H. A. Krebs and K. Henseleit. Untersuchungen uber die harnstoffbildung im tierkorper.Z. Physiol. Chem. 210:33–66 (1932).

  17. 17.

    I. Bekersky. Use of the isolated perfused kidney as a tool in drug disposition studies.Drug Metab. Rev. 14:931–960 (1983).

  18. 18.

    J. M. Nishiitsutsuji-Uwo, B. D. Ross, and H. A. Krebs. Metabolic activities of the isolated perfused rat kidney.Biochem. J. 103:852–862 (1967).

  19. 19.

    R. H. Bowman. The perfused rat kidney.Meth. Enzymol. 39:3–11 (1975).

  20. 20.

    D. E. Smith, E. T. Lin, and L. Z. Benet. Absorption and disposition of furosemide in healthy volunteers, measured with a metabolite-specific assay.Drug Metab. Dispos. 8:337–342 (1980).

  21. 21.

    D. E. Smith and L. Z. Benet. Plasma protein binding of furosemide in kidney transplant patients.J. Pharmacokin. Biopharm. 10:663–674 (1982).

  22. 22.

    H. L. Behm and J. G. Wagner. Errors in interpretation of data from equilibrium dialysis protein binding experiments.Res. Commun. Chem. Pathol. Pharmacol. 26:145–160 (1979).

  23. 23.

    T. N. Tozer, J. G. Gambertoglio, D. E. Furst, D. S. Avery, and N. H. G. Holford. Volume shifts and protein binding estimates using equlibrium dialysis: Application to prednisolone binding in humans.J. Pharm. Sci. 72:1442–1446 (1983).

  24. 24.

    C. M. Metzler. NONLIN, A Computer Program for Parameter Estimation in Nonlinear Situations. Upjohn Co., Kalamazoo, Michigan 1969.

  25. 25.

    B. D. Ross. The isolated perfused rat kidney.Clin. Sci. Mol. Med. 55:513–521 (1978).

  26. 26.

    D. C. Brater and S. O. Thier. Renal disorders. In K. L. Melmon and H. F. Morrelli (eds.),Clinical Pharmacology: Basic Principles in Therapeutics, 2nd ed., Macmillan, New York, 1978, pp. 349–387.

  27. 27.

    R. H. Bowman, J. Dolgin, and R. Coulson. Furosemide, ethacrynic acid, and iodoacetate on function and metabolism in perfused rat kidney.Am. J. Physiol. 224:416–424 (1973).

  28. 28.

    C. G. Duarte, F. Chomety, and G. Giebisch. Effect of amiloride, ouabain, and furosemide on distal tubular function in the rat.Am. J. Physiol 221:632–639 (1971).

  29. 29.

    J. H. Stein, R. C. Mauk, S. Boonjarern, and T. F. Ferris. Differences in the effect of furosemide and chlorothiazide on the distribution of renal cortical blood flow in the dog.J. Lab. Clin. Med. 79:995–1003 (1972).

  30. 30.

    M. D. Bailie, J. A. Barbour, and J. B. Hook. Effects of indomethacin on furosemide-induced changes in renal blood flow.Proc. Soc. Exp. Biol. Med. 148:1173–1176 (1975).

  31. 31.

    E. M. Renkin and J. P. Gilmore. Glomerular filtration. In J. Orloff and R. W. Berliner (eds.),Handbook of Physiology, Section 8,Renal Physiology, American Physiological Society, Washington, D. C., 1973, pp. 185–248.

  32. 32.

    R. Hori, K. Sunayashiki, and A. Kamiya. Tissue distribution and metabolism of drugs. I. Quantitative investigation on renal handling of phenolsulfonphthalein and sulfonamides in rabbits.Chem. Pharm. Bull. 26:740–745 (1978).

  33. 33.

    R. Hori, K. Okumura, A. Kamiya, H. Nihira, and H. Nakano. Ampicillin and cephalexin in renal insufficiency.Clin. Pharmacol. Ther. 34:792–798 (1983).

  34. 34.

    A. Kamiya, K. Okumura, and R. Hori. Quantitative investigation on renal handling of drugs in rabbits, dogs, and humans.J. Pharm. Sci. 72:440–443 (1983).

  35. 35.

    V. P. Hajdú and A. Häussler. Untersuchungen mit dem salidiureticum 4-chloro-N-(2-furylmethyl)-5-sulfamylanthranilsäure, I.Arzneim. Forch. 14:709–710 (1964).

  36. 36.

    J. J. Grantham and J. Irish. Organic transport and fluid secretion in the pars recta (PST) of the proximal tubule. In H. G. Vogel and K. J. Ullrica (eds.),New Aspects of Renal Function, Excerpta Medica, Amsterdam, 1978, pp. 83–87.

  37. 37.

    M. A. Venkatachalam, D. B. Bernard, J. F. Donahope, and N. G. Levinsky. Ischemic damage and repair in the rat proximal tubule: Differences among the S1, S2, and S3 segments.Kidney Int. 14:31–49 (1978).

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Correspondence to David E. Smith.

Additional information

This work was supported in part by the Upjohn Research Fund, College of Pharmacy, University of Michigan. During the course of this work, J.A.C. was supported by a Lilly Endowment Fellowship, grant 830192.

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Lee, L., Cook, J.A. & Smith, D.E. Renal transport kinetics of furosemide in the isolated perfused rat kidney. Journal of Pharmacokinetics and Biopharmaceutics 14, 157–174 (1986). https://doi.org/10.1007/BF01065259

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Key words

  • furosemide
  • protein binding
  • renal and secretion clearances
  • excretion ratio