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Pharmacokinetics of intravenous isosorbide-dinitrate

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Abstract

The kinetics of isosorbide dinitrate (ISDN) after i.v. administration and the absolute availability of an oral slow release preparation (SR) were studied in young healthy volunteers. ISDN and the 2- and 5-mononitrates of isosorbide (2-MN, 5-MN) were determined by GLC. After i.v. administration plasma levels of ISDN declined biexponentially and could be adequately described by an open two compartment body model. Distribution half-life was extremely rapid (2–5 min). Terminal disappearance had a half-life of 67 (62–75) min (mean, range). Total plasma clearance was 1.6 (1.2–2.2) litres · min−1, thus approaching liver blood flow. Nevertheless, absolute systemic availability (F) or oral ISDN amounted to 22% (16–29%). Assuming that oral ISDN is completely absorbed and blood levels do not exceed serum levels, an upper limit of hepatic clearance (liver blood flow 1.5 litres·min−1 · (1-F/100)) can be estimated, which is significantly smaller (p<0.05) than the measured clearance. This finding is best interpreted by assuming that ISDN is partly eliminated by extrahepatic routes, which is further substantiated by a different pattern of metabolites after i.v. and oral dosing. Whereas after i.v. administration more 2-MN is produced, 5-MN is the main metabolite after oral ISDN. Since the glutathione-S-transferases are found in the cytosol of most cells, it seems likely that other organs than the liver contribute to the metabolism of ISDN.

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Authors and Affiliations

  1. Department of Medicine, Inselspital, University of Berne, CH-3010, Bern, Switzerland

    Rudolf Platzer & Renato L. Galeazzi

  2. Department of Ecology, Elektrowatt Ltd., Switzerland

    Georg Reutemann

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  1. Rudolf Platzer
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  2. Georg Reutemann
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  3. Renato L. Galeazzi
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This work was supported in part by a grant from the Swiss National Science Foundation and by a grant-in-aid of the Globopharm AG, Küsnacht, Switzerland.

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Platzer, R., Reutemann, G. & Galeazzi, R.L. Pharmacokinetics of intravenous isosorbide-dinitrate. Journal of Pharmacokinetics and Biopharmaceutics 10, 575–586 (1982). https://doi.org/10.1007/BF01062541

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  • DOI: https://doi.org/10.1007/BF01062541

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