Skip to main content
SpringerLink
Log in

Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion

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

Abstract

Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr±0.7 SD. The mean systemic clearance of ISDN (2.9 L/min ±0.7 SD) and its mean total volume of distribution (259 L +- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml ± 0.9 SD) and of 5-ISMN (27 ng/ml ± 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr± 0.19 SD) and of 5-ISMN (3.78 hr± 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr± 0.41 SD and 5.98 hr± 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.

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. D. T. Danahy, D. T. Burweld, W. S. Aronow, and R. Prakash. Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate.Circulation 55:383–387 (1977).

    Article  Google Scholar 

  2. C. V. Leier, D. F. Bambach, M. J. Thompson, S. M. Cattaneo, R. J. Goldberg, and D. V. Uneverferth. Central and regional hemodynamic effects of intravenous isosorbide dinitrate, nitroglycerin and nitroprusside in patients with congestive heart failure.Am. J. Cardiol. 48:1115–1122 (1981).

    Article  CAS  PubMed  Google Scholar 

  3. A. Distante, A. Maseri, S. Severi, A. Biagini, and S. Chierchia. Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate. A double crossover study in a coronary care unit.Am. J. Cardiol. 44:533–539 (1979).

    Article  CAS  PubMed  Google Scholar 

  4. S. J. Shane, J. J. Iazetta, A. W. Chisholm, J. F. Berka, and D. Leung. Plasma concentrations of isosorbide dinitrate and its metabolites after chronic oral dosage in man.Br. J. Clin. Pharmacol. 6:37–41 (1978).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. M. G. Bogaert and M. T. Rosseel. Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide and isoidide.Arch. Pharmacol. 275:339–342 (1972).

    Article  CAS  Google Scholar 

  6. U. Abshagen and S. Sporl-Radon. First data on effects and pharmacokinetics of isosorbide-5-mononitrate in normal man.Eur. J. Clin. Pharmacol. 19:423–429 (1981).

    Article  CAS  PubMed  Google Scholar 

  7. Y. Santoni, P. H. Rolland, and J. P. Cano. Determination of isosorbide dinitrate and Its mononitrate metabolites in human plasma using Extrelut purification and capillary column GLC.J. Chromatogr. 306:165–172 (1984).

    Article  CAS  PubMed  Google Scholar 

  8. P. A. Cossum and M. S. Roberts. Availability of isosorbide dinitrate, diazepam and chlormethiazole from i.v. delivery systems.Eur. J. Clin. Pharmacol. 19:181–185 (1981).

    Article  CAS  PubMed  Google Scholar 

  9. T. Taylor, L. F. Chasseaud, E. Doyle, R. Bonn, A. Darrach, and R. F. Lambe. Isosorbide dinitrate pharmacokinetics.Arzneim. Forsch./Drug Res. 32:1329–1333 (1982).

    CAS  Google Scholar 

  10. H. G. Boxenbaum, S. Riegelman, and R. M. Elashoff. Statistical estimations in pharmacokinetics.J. Pharmacokin. Biopharm. 2:123–148 (1974).

    Article  CAS  Google Scholar 

  11. T. Taylor, L. F. Chasseaud, and E. Doyle. Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects.Biopharm. Drug Dispos. 1:149–156 (1980).

    Article  CAS  PubMed  Google Scholar 

  12. R. Platzer, G. Reutemann, and R. L. Galeazzi. Pharmacokinetics of intravenous isosorbide dinitrate.J. Pharmacokin. Biopharm. 10:575–586 (1982).

    Article  CAS  Google Scholar 

  13. A. Frydman, J. Levenson, A. Simon, M. Safar, A. Bieder, J. Bertharion, and J. Gaillot. Pharmacocinétique du dinitrate d'isosorbide. Approche après perfusion intraveineuse chez le patient hypertendu.Nouv. Presse Med. 11:2049–2056 (1982).

    CAS  PubMed  Google Scholar 

  14. R. A. Morrison, U. W. Wiegand, E. Jahnchen, D. Hohmann, H. Bechtold, T. Meinertz, and H. L. Fung. Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual and percutaneous dosing in angina.Clin. Pharmacol. Ther. 33:747–756 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. H. Laufen, M. Aumann, and M. Leitold. Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man.Arzneim. Forsch./Drug Res. 33:980–984 (1983).

    CAS  Google Scholar 

  16. L. F. Chasseaud and T. Taylor. Pharmacokinetics of isosorbide mononitrates in human subjects. In Lichtenet al. (eds).,Nitrates III. Cardiovascular Effects, Springer, Berlin, 1981, pp. 47–53.

    Chapter  Google Scholar 

  17. U. Abshagen, G. Betzien, R. Endele, and B. Kaufmann. Pharmacokinetics of intravenous and oral isosorbide-5-mononitrate.Eur. J. Clin. Pharmacol. 20:269–275 (1981).

    Article  CAS  PubMed  Google Scholar 

  18. T. Taylor, L. F. Chasseaud, R. Major, E. Doyle, and A. Darragh. Isosorbide 5-mononitrate pharmacokinetics in humans.Biopharm. Drug Dispos. 2:255–263 (1981).

    Article  CAS  PubMed  Google Scholar 

  19. M. G. Bogaert. Clinical pharmacokinetics of organic nitrates.Clin. Pharmacokin. 8:410–421 (1983).

    Article  CAS  Google Scholar 

  20. P. Sonneveld and J. A. Mulder. Development and identification of multicompartment model for the distribution of adriamycin in the rat.J. Pharmacokin. Biopharm. 9:577–601 (1981).

    Article  CAS  Google Scholar 

  21. Y. Bard,Non-linear Parameter Estimation, Academic Press, New York, 1974, pp. 62–69.

    Google Scholar 

  22. L. B. Sheiner. Analysis of pharmacokinetic data using parametric models—1: Regression models.J. Pharmacokin. Biopharm. 12:93–117 (1984).

    Article  CAS  Google Scholar 

  23. J. G. Wagner.Fundamentals of Clinical Pharmacokinetics, Drug Intelligence, Hamilton, 1975.

    Google Scholar 

  24. R. L. Kashyap. Maximum likelihood identification of stochastic linear systems. IEEE Trans. Autom. Contr.AC-15:25–34 (1970).

    Article  Google Scholar 

  25. A. Iliadis and R. Bruno. Maximum likelihood estimation of a non-linear multi-output pharmacokinetic model: The ethanol-acetate system. In G. C. Vansteenkiste and P. C. Young (eds.),Modelling and Data Analysis in Biotechnology and Medical Engineering, North-Holland, Amsterdam, 1983, pp. 189–197.

    Google Scholar 

  26. D. Goldfarb. A family of variable metric methods derived by variational means.Math. Comput. 24:23–26 (1970).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculté de Pharmacie, INSERM U278, 27, bd. Jean Moulin, 13385, Marseille Cedex 5, France

    Yves Santoni, Athanassios Iliadis & Jean -Paul Cano

  2. CHU Nord, Service de Médecine Interne et des Urgences, 13326, Marseille, France

    Roger Luccioni & Yves Frances

Authors
  1. Yves Santoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athanassios Iliadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean -Paul Cano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger Luccioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Frances
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santoni, Y., Iliadis, A., Cano, J.P. et al. Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion. Journal of Pharmacokinetics and Biopharmaceutics 14, 1–17 (1986). https://doi.org/10.1007/BF01059280

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01059280

Key words

Search

Navigation