Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung

Philip R. Mayer, William Charles Lubawy, Patrick J. McNamara, Harry B. Kostenbauder

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000Xg supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5‐isosorbide mononitrate, 2‐isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000Xg supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near‐simultaneous cleavage of both nitrate ester groups. Intravascular multiple‐dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.

Original languageEnglish
Pages (from-to)785-789
Number of pages5
JournalJournal of Pharmaceutical Sciences
Volume72
Issue number7
DOIs
StatePublished - 1 Jan 1983

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Isosorbide Dinitrate
Rabbits
Lung
Isosorbide
isosorbide-5-mononitrate
Nitrates
Esters
Perfusion

Keywords

  • Isosorbide dinitrate—metabolism in isolated perfused rabbit lung, kinetic profiles
  • Metabolism—of isosorbide dinitrate and metabolites in isolated perfused rabbit lung, kinetic profiles
  • Metabolites—of isosorbide dinitrate, kinetic profiles in isolated perfused rabbit lung

Cite this

Mayer, P. R., Lubawy, W. C., McNamara, P. J., & Kostenbauder, H. B. (1983). Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung. Journal of Pharmaceutical Sciences, 72(7), 785-789. https://doi.org/10.1002/jps.2600720717
Mayer, Philip R. ; Lubawy, William Charles ; McNamara, Patrick J. ; Kostenbauder, Harry B. / Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung. In: Journal of Pharmaceutical Sciences. 1983 ; Vol. 72, No. 7. pp. 785-789.
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abstract = "The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000Xg supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5‐isosorbide mononitrate, 2‐isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000Xg supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near‐simultaneous cleavage of both nitrate ester groups. Intravascular multiple‐dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.",
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Mayer, PR, Lubawy, WC, McNamara, PJ & Kostenbauder, HB 1983, 'Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung', Journal of Pharmaceutical Sciences, vol. 72, no. 7, pp. 785-789. https://doi.org/10.1002/jps.2600720717

Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung. / Mayer, Philip R.; Lubawy, William Charles; McNamara, Patrick J.; Kostenbauder, Harry B.

In: Journal of Pharmaceutical Sciences, Vol. 72, No. 7, 01.01.1983, p. 785-789.

Research output: Contribution to journalArticle

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T1 - Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung

AU - Mayer, Philip R.

AU - Lubawy, William Charles

AU - McNamara, Patrick J.

AU - Kostenbauder, Harry B.

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N2 - The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000Xg supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5‐isosorbide mononitrate, 2‐isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000Xg supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near‐simultaneous cleavage of both nitrate ester groups. Intravascular multiple‐dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.

AB - The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000Xg supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5‐isosorbide mononitrate, 2‐isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000Xg supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near‐simultaneous cleavage of both nitrate ester groups. Intravascular multiple‐dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.

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