Skip to main content
SpringerLink
Log in

Evaluation of potential causes for the incomplete bioavailability of furosemide: Gastric first-pass metabolism

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

Potential causes for reported incomplete (usually 40–60%) and often highly variable (e.g., 11–79%) bioavailability of furosemide in humans were investigated. The drug was found to be fairly stable in gastric fluids and its hepatic first-pass elimination (HFPE) was estimated to be much less than 6% based on published i.v. data. The rat was used as the main model for extensive evaluation. About 4% (n=4) of dose was recovered unchanged in the GI tract after i.v. injection while about 40% (n=12) was recovered after a 120-fold (0.05–6 mg) dose range of oral administration. In another study 70 % of the oral dose eventually disappearing (presumably due to absorption and first-pass elimination) from the GI tract was estimated to occur in just 20 min. These data indicate an unsaturable, incomplete, site-specific absorption as well as a lack of dissolution-rate-limited absorption at the doses studied. Based on plasma data, oral bioavailability in four rats was only 30%, and the HFPE much <10%. After oral administration, 61% of the dose was absorbed and/or metabolized in the GI recovery study. Thus, 20–30% of oral dose in rats must be metabolized in the GI wall during absorption. The metabolic activity of stomach (homogenate) from 5 rats was found to be much (e.g., 5–10.5-fold) greater than those of liver and small intestine. This was also confirmed in preliminary studies with 3 rabbits and 1 dog. Large intersubject variability in enzyme activity was found in rats and rabbits. The phenomenon of a presystemic first-pass effect was also substantiated by urinary excretion data of a metabolite. It is postulated that variable gastric and intestinal first-pass metabolism may be a major factor causing incomplete and irregular absorption of furosemide in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. M. R. Kelly, R. E. Cutler, A. W. Forrey, and B. M. Kimpel. Pharmacokinetics of orally administered furosemide.Clin. Pharmacol. Ther. 15:178–186 (1974).

    CAS  PubMed  Google Scholar 

  2. E. S. Waller, S. F. Hamilton, J. W. Massarella, M. A. Sharanevych, R. V. Smith, G. J. Yakatan, and J. T. Doluisio. Disposition and absolute bioavailability of furosemide in healthy males.J. Pharm. Sci. 71:1105–1108 (1982).

    Article  CAS  PubMed  Google Scholar 

  3. W. Rupp. Pharmacokinetics and pharmacodynamics of Lasix.Scott. Med. J. 19:5–13 (1973).

    Google Scholar 

  4. R. A. Branch, C. J. C. Roberts, M. Homeida, and D. Levine. Determinants of response to furosemide in normal subjects.Br. J. Clin. Pharmacol. 4:121–127 (1977).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. A. Rane, J. P. Villeneuve, W. J. Seone, A. S. Nies, G. R. Wilkinson, and R. A. Branch. Plasma binding and disposition of furosemide in the nephrotic syndrome and uremia.Clin. Pharmacol. Ther. 24:199–207 (1978).

    CAS  PubMed  Google Scholar 

  6. B. Beermann, E. Dalén, B. Lindstrom, and A. Rosén. On the fate of furosemide in man.Eur. J. Clin. Pharmacol. 9:57–61 (1975).

    Article  CAS  Google Scholar 

  7. D. E. Smith, E. C. Lin, and L. Z. Benet. Absorption and disposition of furosemide in healthy volunteers, measured with a metabolic-specific assay.Drug Metab. Dispos. 8:337–342 (1981).

    Google Scholar 

  8. D. C. Brater, R. Seiwell, S. Andreasen, A. Burdette, G. J. Dekmer, and P. Chennavasin. Absorption and disposition of furosemide in congestive heart failure.Kidney Int. 22:171–176 (1982).

    Article  CAS  PubMed  Google Scholar 

  9. C. M., Huang, A. J. Atkinson, Jr., M. Levin, and A. Quintanilla. Pharmacokinetics of furosemide in advanced renal failure.Clin. Pharmacol. Ther. 16:659–666 (1974).

    CAS  PubMed  Google Scholar 

  10. A. Greither, S. Goldman, J. S. Edelen, L. Z. Benet, and K. Cohn. Absorption of furosemide in patients with congestive heart failure.Pharmacology 19:121–131 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. M. R. Kelly, A. D. Blair, A. W. Forrey, N. A. Smidt, and R. A. Cutler. A comparison of the diuretic response to oral and intravenous furosemide in “diuretic-resistant‘ patients.Curr. Ther. Res. 21:1–9 (1977).

    CAS  PubMed  Google Scholar 

  12. G. J. Yakatan, D. D. Maness, J. Scholler, J. T. Johnson, W. J. Novick, Jr., and J. T. Doluisio. Plasma and tissue levels of furosemide in dogs and monkeys following single and multiple oral doses.Res. Commun. Chem. Pathol. Pharmacol. 24:465–482 (1979).

    CAS  PubMed  Google Scholar 

  13. G. J. Yakatan, D. D. Maness, J. Scholler, W. J. Novick, Jr., and J. T. Doluisio. Absorption, distribution, metabolism, and excretion of furosemide in dogs and monkeys I. Analytical methodology, metabolism, and urinary excretion.J. Pharm. Sci. 65:1456–1460 (1976).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. V. S. Chungi, L. W. Dittert, and R. B. Smith. Gastrointestinal sites of furosemide absorption in rats.Int. J. Pharm. 4:27–38 (1979).

    Article  CAS  Google Scholar 

  17. J. E. Cruz, D. D. Maness, and J. G. Yakatan. Kinetics and mechanism of hydrolysis of furosemide.Int. J. Pharm. 2:275–281 (1979).

    Article  CAS  Google Scholar 

  18. F. Andreasen, H. E. Boetker, and K. Lorentzen.In vitro studies in the hydrolysis of furosemide in gastrointestinal juices.Br. J. Clin. Pharmacol 14:306–309 (1982).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Remington's Pharmaceutical Sciences, 15th ed. Mack Publishing Co., Easton, Pa., 1975, p. 872.

  20. J. Honari, A. D. Blair, and R. E. Cutler. Effect of probenecid on furosemide kinetics and natriuresis in man.Clin. Pharmacol. Ther. 22:395–401 (1977).

    CAS  PubMed  Google Scholar 

  21. F. Andreasen, O. L. Pedersen, and E. Mikkelsen. Distribution, elimination, and natriuretic effect of furosemide in patients with severe arterial hypertension.Eur. J. Clin. Pharmacol. 14:237–244 (1978).

    Article  CAS  PubMed  Google Scholar 

  22. M. G. Lee, M. L. Chen, and W. L. Chiou. Pharmacokinetics of drugs in blood II: Unusual distribution and storage effect of furosemide.Res. Commun. Chem. Pathol. Pharmacol. 34:17–28 (1981).

    CAS  PubMed  Google Scholar 

  23. M. L. Chen, M. G. Lee, and W. L. Chiou. Pharmacokinetics of drugs in blood III: Metabolism of procainamide and storage effect of blood samples.J. Pharm. Sci. 72:572–574 (1983).

    Article  CAS  PubMed  Google Scholar 

  24. C. L. Litterst, E. G. Mimnaugh, R. I. Reagan, and T. E. Gram. Comparison ofin vitro drug metabolism by lung, liver and kidney of several common laboratory species.Drug Metab. Dispos. 3:259–265 (1975).

    CAS  PubMed  Google Scholar 

  25. R. L. Nation, G. W. Peng, and W. L. Chiou. Quantitative analaysis of furosemide in microplasma volumes by high performance liquid column chromatography.J. Chromatogr. Biomed. Appl. 162:88–93 (1979).

    Article  CAS  Google Scholar 

  26. M. G. Lee. Absorption and disposition of furosemide. Ph.D. thesis, University of Illinois, Chicago, 1982.

    Google Scholar 

  27. M. L. Chen, G. Lam, M. G. Lee, and W. L. Chiou. Arterial and venous blood sampling in pharmacokinetic studies: Griseofulvin.J. Pharm. Sci. 71:1386–1389 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. W. L. Chiou. Critical evaluation of potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve.J. Pharmacokin. Biopharm. 6:539–546 (1978).

    Article  CAS  Google Scholar 

  29. M. Gibaldi and D. Perrier.Pharmacokinetics, 2nd ed. Marcel Dekker, New York, 1982, p. 332.

    Google Scholar 

  30. H. J. Baker, J. R. Lindsey, and S. H. Weisbroth.The Laboratory Rat. Vol. I. Biology and Diseases. Academic Press, New York, 1979, p. 87.

    Google Scholar 

  31. W. L. Chiou, C. Y. Lui, and G. Lam. Limitation of the plasma area method in the relative bioavailability evaluation of drugs with changing biological half-lives.J. Pharm. Sci. 70:109–112 (1981).

    Article  CAS  PubMed  Google Scholar 

  32. K. C. Kwan and A. E. Till. Novel method for bioavailability assessment.J. Pharm. Sci. 7:527–536 (1979).

    Google Scholar 

  33. S. Øie and D. Jung. Bioavailability under variable renal clearance conditions.J. Pharm. Sci. 68:128–129 (1979).

    Article  PubMed  Google Scholar 

  34. W. L. Chiou. New calculation method for mean apparent drug volume of distribution and application to rational dosage regimens.J. Pharm. Sci. 68:1067–1069 (1979).

    Article  CAS  PubMed  Google Scholar 

  35. R. Fuller, C. Hoppel, and S. T. Ingalls. Furosemide kinetics in patients with hepatic cirrhosis with ascites.Clin. Pharmacol. Ther. 30:461–467 (1981).

    Article  CAS  PubMed  Google Scholar 

  36. R. K. Verbeeck, J. F. Gerkens, G. P. Wilkinson, and R. A. Branch. Disposition of furosemide in functionally hepatectomized dogs.J. Pharmacol. Exp. Ther.,216:479–483 (1981).

    CAS  PubMed  Google Scholar 

  37. M. M. Hammarlund and L. K. Paalzow. Dose-dependent pharmacokinetics of furosemide in the rat.Biopharm. Drug Dispos. 3:345–359 (1982).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. T. P. Green and B. L. Mirkin. Furosemide disposition in normal and proteinuric rats: urinary drug-protein binding as a determinant of drug excretion.J. Pharmacol. Exp. Ther. 218:122–127 (1981).

    CAS  PubMed  Google Scholar 

  40. S. Inui, M. Yamamoto, H. Nakae, and S. Asada. Dose dependency of loop diuretics, furosemide and piretanide in the rat.Yakugaku Zasshi. 102:1053–1060 (1982).

    CAS  PubMed  Google Scholar 

  41. C. Lambert, G. Caille, and P. Du Souich. Nonrenal clearance of furosemide as a course of diuretic response variability in the rat.J. Pharmacol. Exp. Ther. 222:232–236 (1982).

    CAS  PubMed  Google Scholar 

  42. J. D. Wallin, P. Ryals, and N. Kaplowicz. Metabolic clearance of furosemide in the rat.J. Pharmacol. Exp. Ther. 200:52–57 (1977).

    CAS  PubMed  Google Scholar 

  43. P. C. Rowbotham, J. B. Stanford, and J. K. Sugden. Some aspects of the photochemical degradation of furosemide.Pharm. Acta Helv. 51:304–307 (1976).

    CAS  Google Scholar 

  44. S. M. Huang, Y. C. Huang, and W. L. Chiou. Oral absorption and presystemic first pass effect of chlorpheniramine in rabbits.J. Pharmacokin. Biopharm. 9:725–738 (1981).

    Article  CAS  Google Scholar 

  45. V. K. Prasad, R. S. Rapaka, P. W. Knight, and B. E. Cabana. Dissolution medium—a critical parameter to identify bioavailability problems of furosemide tablets.Int. J. Pharm.,11:81–90 (1982).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University of Illinois, 60612, Chicago, Illinois

    Myung G. Lee & Win L. Chiou

Authors
  1. Myung G. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Win L. Chiou
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This paper is taken from a dissertation submitted by Myung G. Lee to the Graduate College, University of Illinois, in partial fulfillment of Doctor of Philosophy Degree requirements.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, M.G., Chiou, W.L. Evaluation of potential causes for the incomplete bioavailability of furosemide: Gastric first-pass metabolism. Journal of Pharmacokinetics and Biopharmaceutics 11, 623–640 (1983). https://doi.org/10.1007/BF01059061

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01059061

Key words

Search

Navigation