Clinical Pharmacokinetics

, Volume 13, Issue 5, pp 334–343 | Cite as

Clinical Pharmacokinetic Significance of the Renal Tubular Secretion of Digoxin

  • Gideon Koren
Research Review

Summary

Tubular secretion appears to be a major route of the renal elimination of digoxin. Secretion of the drug by the tubules is modulated by renal blood flow, by a number of commonly coadministered drugs (e.g. quinidine, spironolactone, verapamil, amiodarone), and by age. The maximal transport capacity does not appear to be achieved with clinically relevant concentrations. The tubular transport of digoxin does not appear to be associated with the anionic or cationic transport systems, nor the Na+/K+-ATPase receptor.

Further studies are needed to elucidate the exact mechanisms involved in the transtubular movement of the glycoside.

Keywords

Digoxin Inulin Quinidine Spironolactone Renal Blood Flow 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aronson JK. An account of the foxglove and some of its medical uses, 1785–1985, Oxford Medical Publication, Oxford 1985Google Scholar
  2. Belz GG, Doering W, Munkew R, Matthews J. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clinical Pharmacology and Therapeutics 33: 410–417, 1983PubMedCrossRefGoogle Scholar
  3. Cogan JJ, Humphreys MH, Carlson J, Benowitz NL, Rapaport E. Acute vasodilator therapy increases renal clearance of digoxin in patients with congestive heart failure. Circulation 64: 973–976, 1981PubMedCrossRefGoogle Scholar
  4. Doherty JE, Ferrel CB, Towbin EJ. Localization of the renal excretion of the tritiated digoxin. American Journal of the Medical Sciences 258: 181–189, 1969aPubMedCrossRefGoogle Scholar
  5. Doherty JE, Flanigan WJ, Patterson RM, Dalrymple GV. The excretion of tritiated digoxin in normal human volunteers before and after unilateral nephrectomy. Circulation 40: 555–561, 1969bPubMedCrossRefGoogle Scholar
  6. Doherty JE, Perkins WH, Mitchell GK. Tritiated digoxin studies in human studies. Archives of Internal Medicine 108: 531–539, 1961PubMedCrossRefGoogle Scholar
  7. Fenster PE, Hager WD, Goodman MM. Digoxin-quinidine-spironolactoñe interaction. Clinical Pharmacology and Therapeutics 36: 70–73, 1984PubMedCrossRefGoogle Scholar
  8. Fenster PE, White NW, Hanson CD. Pharmacokinetic evaluation of the digoxin-amiodarone interaction. Journal of the American College of Cardiology 5: 108–112, 1985PubMedCrossRefGoogle Scholar
  9. Finch MB, Johnston GD, Kelly JG, McDevitt DG. Pharmacokinetics of digoxin alone and in the presence of indomethacin therapy. British Journal of Clinical Pharamacology 17: 353–399, 1984CrossRefGoogle Scholar
  10. Gault MH, Longerich L, Loo JCK. Digoxin biotransformation. Clinical Pharmacology and Therapeutics 35: 74–82, 1984PubMedCrossRefGoogle Scholar
  11. Gibson TP, Quintanilla A. Effect of quinidine on the renal handling of digoxin. Journal of Laboratory and Clinical Medicine 96: 1062–1070, 1980PubMedGoogle Scholar
  12. Gibson TP, Quintanilla AP. Effect of volume expansion, furosemide and diuresis on the renal clearance of digoxin. Journal of Pharmacology and Experimental Therapeutics 219: 54–59, 1981PubMedGoogle Scholar
  13. Gibson TP, Ribner HS, Quintanilla AP. Effect of acute changes in serum digoxin concentration on renal digoxin clearance. Clinical Pharmacology and Therapeutics 36: 478–484, 1984PubMedCrossRefGoogle Scholar
  14. Goldfrank LR. Toxicologic emergencies. Appleton-Century-Crofts, New York, 1986Google Scholar
  15. Hager WD, Fenster P, Mayersohn M, Perrier D, Graves P, et al. Digoxin quinidine interaction: pharmacokinetic evaluation. New England Journal of Medicine 300: 1238–1241, 1979PubMedCrossRefGoogle Scholar
  16. Hastreiter AR, Van Der Horst RL. Postmortem digoxin tissue concentration and organ content in infancy and childhood. American Journal of Cardiology 52: 330–335, 1985CrossRefGoogle Scholar
  17. Klein HO, Lang R, Di Segni E, Kaplinsky E. Verapamil-digoxin interaction. New England Journal of Medicine 303: 160, 1980PubMedGoogle Scholar
  18. Koren G. Interaction between digoxin and commonly co-administered drugs in children. Pediatrics 75: 1032–1037, 1985PubMedGoogle Scholar
  19. Koren G, Hesslein PD, MacLeod SM. Digoxin toxicity associated with amiodarone in children. Journal of Pediatrics 104: 467–471, 1984aPubMedCrossRefGoogle Scholar
  20. Koren G, Klein J, Ben Dayan R, MacLeod SM, Silverman M. Simultaneous inhibition of the renal and biliary transport of digoxin by quinidine. Clinical and Investigative Medicine, in press, 1987Google Scholar
  21. Koren G, Klein J, MacLeod SM, Silverman M. Digoxin handling by the renal tubular cell. Clinical and Investigative Medicine 9: A16, 1986aGoogle Scholar
  22. Koren G, Klein J, MacLeod SM, Silverman M. Digoxin handling by the renal tubular cell. Clinical Research 34: 867A, 1986bGoogle Scholar
  23. Koren G, MacLeod SM, Silverman M. Application of novel in vivo and in vitro methods to the study of renal digoxin handling. Abstract No. 1034, Proceedings of the III World Conference on Clinical Pharmacology and Therapeutics, Stockholm, 1986cGoogle Scholar
  24. Koren G, Parker R. Interpretation of excessive serum concentrations of digoxin in children. American Journal of Cardiology 55: 1210–1214, 1985PubMedCrossRefGoogle Scholar
  25. Koren G, Soldin S, MacLeod SM. Digoxin-verapamil interaction: in vitro studies in rat tissue. Journal of Cardiovascular Pharmacology 5: 443–446, 1983aPubMedCrossRefGoogle Scholar
  26. Koren G, Soldin S, MacLeod SM. Digoxin-amiodarone interaction: in vivo and in vitro studies in rat tissues. Canadian Journal of Physiology and Pharmacology 61: 1483–1486, 1983bPubMedCrossRefGoogle Scholar
  27. Koren G, Soldin S, MacLeod SM. Interaction of digoxin with verapamil, indomethacin and other co-administered drugs: a comparative study in rat tissue. In MacLeod et al. (Eds). Proceedings of the International Congress of Developmental Pharmacology, Toronto, October 1982, pp. 417–420, Allan R. Liss Inc, New York, 1983cGoogle Scholar
  28. Koren G, Zarfin Y, Perlman M, MacLeod SM. The influence of indomethacin on digoxin pharmacokinetics in preterm infants. Pediatric Pharmacology 4: 25–30, 1984bPubMedGoogle Scholar
  29. Leahey BJ, Reiffei JA, Drusin RE, Heisenbuttel RH, Bigger TP. Interaction between quinidine and digoxin. Journal of the American Medical Association 240: 533–536, 1978PubMedCrossRefGoogle Scholar
  30. Linday LA, Engle MA, Reidenberg MM. Maturation and renal digoxin clearance. Clinical Pharmacology and Therapeutics 30: 735–738, 1981PubMedCrossRefGoogle Scholar
  31. Lukas DS, De Martino AG. Binding of digitoxin and some related cardenolides to human plasma proteins. Journal of Clinical Investigation 48: 1041–1053, 1969PubMedCrossRefGoogle Scholar
  32. Maragno J, Santostasi G, Gaion RM, Paleari C. Influence of amiodarone on oral digoxin bioavailability in healthy volunteers. International Journal of Clinical Pharmacology Research 4: 149–153, 1984PubMedGoogle Scholar
  33. Milton A, Odling B, Dencker L. Renal handling and effects of 3H digoxin and interactions with quinidine in the avian kidney. Acta Physiologica Scandinavica 127: 9–16, 1986PubMedCrossRefGoogle Scholar
  34. Moysey JO, Jaggarao NSU, Grundy EN. Amiodarone increases plasma digoxin concentrations. British Medical Journal 282: 272–273, 1981PubMedCrossRefGoogle Scholar
  35. Mulrow CC, Feussner JR, Velez R. Reevaluation of digitalis efficacy. Annals of Internal Medicine 101: 113–117, 1984PubMedGoogle Scholar
  36. Nier AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and drug disposition. In Gibaldi and Prescott (Eds) Handbook of clinical pharmacokinetics, section I, pp. 77–96, ADIS Health Science Press, Syndey, 1983Google Scholar
  37. O’Brien MS, Salomone LF, Gibson TP. Effect of spironolactone on the renal clearance of digoxin in dogs. Journal of Pharmacology and Experimental Therapeutics 234: 190–194, 1985PubMedGoogle Scholar
  38. Ogilvie RI, Dorian P, Strauss M, Cardella C, David T. Digoxincyclosporine interaction: a new phenomenon. Abstract No. 1100, Proceedings of the III World Conference on Clinical Pharmacology & Therapeutics, Stockholm, 1986Google Scholar
  39. Ohnhaus EE, Sprung P, Dettli L. Protein binding of digoxin in human serum. European Journal of Clinical Pharmacology 5: 35–39, 1972CrossRefGoogle Scholar
  40. Pedersen KE. Digoxin interactions. Acta Medica Scandinavica (Supp. 697): 1–40, 1985Google Scholar
  41. Pedersen KE, Dorph Pederson A, Huidt S, Klitgaard UN, Nielsen Kudsk F. Digoxin-verapamil interaction: a single dose pharmacokinetic study. Clinical Pharmacology and Therapeutics 30: 311–317, 1981PubMedCrossRefGoogle Scholar
  42. Pedersen KE, Madsen JL, Klitgaard NA, Kjaer K, Hvidt S. Effect of quinine on plasma digoxin concentration and renal digoxin clearance. Acta Medica Scandinavica 218: 229–232, 1985PubMedCrossRefGoogle Scholar
  43. Rameis H. Quinidine-digoxin interaction: are the pharmacokinetics of both drugs altered. International Journal of Clinical Pharmacology and Therapeutics Toxicology 23: 145–153, 1985Google Scholar
  44. Rameis H, Magometschnigg D, Ganzinger U. The diltiazem-digoxin interaction. Clinical Pharmacology and Therapeutics 36: 183–189, 1984PubMedCrossRefGoogle Scholar
  45. Rennick B, Quabbenzann AJ. Renal tubular excretion of drugs: proximal tubule and metabolism. In Fisher & Cafruny (Eds). Renal pharmacology, p. 68, Appleton-Century-Crofts, New York, 1971Google Scholar
  46. Roman JR, Kauker LM. Renal tubular transport of H3 digoxin in saline diuresis in rats: evaluation by micropuncture. Circulation Research 38: 185–191, 1976PubMedCrossRefGoogle Scholar
  47. Schenck Gustafsson KD, Juhlin Dannfelt A, Dahlquist R. Renal function and digoxin clearance during quinidine therapy. Clinical Physiology 2: 410–418, 1982CrossRefGoogle Scholar
  48. Schwartz JB, Migliore PJ. Effect of nifedipine on serum digoxin concentration and renal digoxin clearance. Clinical Pharmacology and Therapeutics 36: 19–24, 1984PubMedCrossRefGoogle Scholar
  49. Schwartz ZA. Is the cell membrane Na+/K+-ATPase enzyme system the pharmacological receptor for digitalis? Circulation Research 39: 2–7, 1976CrossRefGoogle Scholar
  50. Silverman M, Trainor C. In vivo determination of cellular uptake in the kidney. Federation Proceedings 41: 3054–3060, 1982PubMedGoogle Scholar
  51. Soldin SJ. Digoxin — issues and controversies. Clinical Chemistry 32: 5–12, 1986PubMedGoogle Scholar
  52. Steiness E. Renal tubular secretion of digoxin. Circulation 50: 103–107, 1974PubMedCrossRefGoogle Scholar
  53. Steiness E, Waldorff S, Hansen PB. Renal digoxin clearance: dependence on plasma digoxin and diuresis. European Journal of Clinical Pharmacology 23: 151–154, 1982PubMedCrossRefGoogle Scholar
  54. Tallardia RJ. Most prescribed drugs 1985, WB Saunders Co., Philadelphia, 1985Google Scholar
  55. Waldorff S, Hansen PB, Egeblod H, Berning J, Buch J, et al. Interactions between digoxin and potassium-sparing diuretics. Clinical Pharmacology and Therapeutics 33: 418–423, 1983PubMedCrossRefGoogle Scholar
  56. Waldorff S, Hansen PB, Kjaergard H, Buch J, Egeblod H, et al. Amiloride-induced changes in digoxin pharmacokinetics and kinetics. Clinical Pharmacology and Therapeutics 30: 172–176, 1981PubMedCrossRefGoogle Scholar
  57. Wandell M, Powell JR, Hager WD, Fenster PE, Graves PE, et al. Effect of quinine on digoxin kinetics. Clinical Pharmacology and Therapeutics 28: 425–430, 1980PubMedCrossRefGoogle Scholar
  58. Wilkerson D, Mockridge PB, Massing GK. Effects of selected drugs on serum digoxin concentration in dogs. American Journal of Cardiology 45: 1201–1210, 1980PubMedCrossRefGoogle Scholar
  59. Wilson DM. Tests of renal function. In Frohnert (Ed.) Clinical Medicine, Vol. 7, Harpers Row, Philadelphia, 1985Google Scholar
  60. Yoshida A, Fujita M, Kurosawa N, Nioka M, Shichimoke T, et al. Effect of diltiazem on plasma level and urinary excretion of digoxin in healthy subjects. Clinical Pharmacology and Therapeutics 35: 681–685, 1984PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • Gideon Koren
    • 1
    • 2
  1. 1.Department of Clinical PharmacologyThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of PediatricsUniversity of TorontoTorontoCanada

Personalised recommendations