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Biotransformation of Organic Nitrates

  • Philip Needleman
Part of the Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology book series (HEP, volume 40)

Abstract

The investigation of organic nitrate biotransformation began with the observation by Hay (1883) and by Crandall (1929, 1933) that inorganic nitrite appears after incubation of glyceryl trinitrate (GTN) with blood. CrandallCrandall et al. (1929) demonstrated that GTN rapidly disappeared from the circulation after intravenous administration to dogs and inorganic nitrite could be qualitatively detected. Yagoda and von Oettingen (1944) incubated GTN, erythrityl tetranitrate (ETN), and pentaerythrityl tetranitrate (PETN) with dog blood and demonstrated the formation of inorganic nitrite.

Keywords

Nitrate Reductase Urinary Metabolite Isosorbide Dinitrate Organic Nitrate Pentaerythritol Tetranitrate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Al-Kassab, S., Boyland, E., Williams, K.: An enzyme from rat liver catalyzing conjugations with glutathione. 2. Replacement of nitro groups. Biochem. J. 87, 4–9 (1963).PubMedGoogle Scholar
  2. Ansorge, S., Bohley, R., Kirschke, H., Langner, J., Wiederanders, B., Hanson, H.: Metabolism of insulin and glucagon. Glutathione-insulin transhydrogenase from microsomes of rat liver. Europ. J. Biochem. 32, 27–35 (1973).PubMedCrossRefGoogle Scholar
  3. Betts, J. J., Bray, H.G., James, S.P., Thorpe, W.V.: The metabolism of the trichloronitrobenzenes in the rabbit. Biochem. J. 66, 610–621 (1957).PubMedGoogle Scholar
  4. Blum, S.W., Quinn, J.B., Howe, B.B., Hefner, M.A., Winbury, M.M.: Pharmacologic and biochemical evaluation of organic nitrates: Attempted correlation of activities. J. Pharmacol. exp. Ther. 176, 684–691 (1971).PubMedGoogle Scholar
  5. Bogaert, M.G., Rosseel, M.T.: Plasma levels in man of nitroglycerin after buccal administration. J. Pharm. Pharmacol. 24, 737–738 (1972 a).PubMedCrossRefGoogle Scholar
  6. Bogaert, M.G., Rosseel, M.T.: Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide, and isoidide. Arch. Pharmacol. 275, 339–342 (1972 b).CrossRefGoogle Scholar
  7. Bogaert, M. G., Rosseel, M.T., Belpaire, F.M.: Metabolism of nitroglycerin in man. Influence of phenobarbital. Arch. int. Pharmacodyn. Ther. 192, 198–199 (1971).PubMedGoogle Scholar
  8. Bogaert, M.G., Rosseel, M.T., Schaepdryver, A.F. De: Cardiovascular effects of glyceryl dinitrates as compared to glyceryl trinitrate. Arch. int. Pharmacodyn. 176, 458–460 (1968).PubMedGoogle Scholar
  9. Bogaert, M.G., Rosseel, M.T., Schaepdryver, A.F., De: Excretion in urine of metabolites of glyceryl trinitrate in rabbits. Arch. int. Pharmadocyn. Ther. 179, 480–489 (1969 a).Google Scholar
  10. Bogaert, M. G., Rosseel, M.T., Schaepdryver, A. F., De: Biotransformation of glyceryl trinitrate in rabbits. Arch. int. Pharmacodyn. Ther. 177, 487–491 (1969b).PubMedGoogle Scholar
  11. Bogaert, M.G., Rosseel, M.T., Schaepdryver, A.F., De: Metabolic fate of nitroglycerin in relation to its vascular effects. Europ. J. Pharmacol. 12, 224–230 (1970).CrossRefGoogle Scholar
  12. Booth, J., Boyland, E., Sims, P.: An enzyme from rat liver catalyzing conjugations with glutathione. Biochem. J. 79, 516–524 (1961).PubMedGoogle Scholar
  13. Bray, H.G., Hybs, Z., James, S.P., Thorpe, W. V.: The metabolism of 2,3,5,6- and 2,3,4,5-tetrachloronitrobenzene in the rabbit and the reduction of aromatic nitro compounds in the intestine. Biochem. J. 53, 266–273 (1953).PubMedGoogle Scholar
  14. Clark, D.G., Litchfield, M.H.: Metabolism of ethylene glycol dinitrate and its influence on the blood pressure of the rat. Brit. J. Industr. Med. 24, 320–325 (1967).PubMedGoogle Scholar
  15. Clark, D.G., Litchfield, M.H.: The toxicity, metabolism, and pharmacologic properties of propylene glycol 1,2-dinitrate. Toxicol. Appl. Pharmacol. 15, 175–184 (1969).PubMedCrossRefGoogle Scholar
  16. Combes, B., Stakelum, G.S.: A liver enzyme that conjugates sulfobromophthalein sodium with glutathione. J. clin. Invest. 40, 981–990 (1961).PubMedCrossRefGoogle Scholar
  17. Commarato, M.A., Winbury, M.M., Kaplan, H.R.: Glyceryl trinitrate and pentrinitrol (pentaerythritol trinitrate): Comparative cardiovascular effects in dog, cat and rat by different routes of administration. J. Pharmacol. exp. Ther. 187, 300–307 (1973).PubMedGoogle Scholar
  18. Crandall, L.A., Jr.: The fate of glyceryl trinitrate in the tolerant and non-tolerant animal. J. Pharmacol. exp. Ther. 48, 127–140 (1933).Google Scholar
  19. Crandall, L.A., Jr., Leake, C.D., Loevenhart, A.S., Muehlberger, C.W.: The rate of elimination of glyceryl trinitrate from the blood stream after intravenous administration in dogs. J. Pharmacol. exp. Ther. 37, 283–296 (1929).Google Scholar
  20. Crew, M.C., Gala, R.L., Haynes, L.J., Di Carlo, F.J.: Biliary excretion and biotransformation of pentaerythritol trinitrate in rats. Biochem. Pharmacol. 20, 3077–3089 (1971).PubMedCrossRefGoogle Scholar
  21. Davidson, I.W.F., Miller, H.S., Jr., Di Carlo, F.J.: Absorption, excretion and metabolism of pentaerythritol tetranitrate by humans. J. Pharmacol. exp. Ther. 175, 42–50 (1970).PubMedGoogle Scholar
  22. Davidson, I.W.F., Miller, H.S., Jr., DiCarlo, F.J.: Pharmacodynamics and biotransformation of pentaerythritol tetranitrate in man. J. Pharm. Sci. 60, 274–277 (1971).PubMedCrossRefGoogle Scholar
  23. Davidson, I.W.F., Rollins, F.O., Dicarlo, F. J., Miller, H.S., Jr.: The pharmacodynamics and biotransformation of pentaerythritol trinitrate in man. Clin. Pharmacol. Ther. 12, 972–981 (1971).PubMedGoogle Scholar
  24. De Lorenzo, F., Goldberger, R.F., Steers, E., Jr., Givol, D., Anfinsen, C.B.: Purification and properties of an enzyme from beef liver which catalyzes sulfhydryl-disulfîde interchange inproteins. J. biol. Chem. 241, 1562–1567 (1966).PubMedGoogle Scholar
  25. DiCarlo, F.J., Coutinko, C.B., Crew, M.C.: Sites of absorption of pentaerythritol tetranitrate. Arch. int. Pharmacodyn. 167, 163–170 (1967 a).Google Scholar
  26. DiCarlo, F.J., Coutinko, C.B., Sklow, N.J., Haynes, L.J., Crew, M.C.: Binding of pentaerythritol tetranitrate and its metabolites by rat blood plasma and erythrocytes. Proc. Soc. exp. Biol. (N.Y.) 120, 705–709 (1965 b).Google Scholar
  27. DiCarlo, F.J., Crew, M.C., Coutinko, C.B., Haynes, L.J., Sklow, N.J.: The absorption and biotransformation of pentaerythritol tetranitrate-1,2–14C by rats. Biochem. Pharmacol. 16, 309–316 (1967 b).CrossRefGoogle Scholar
  28. DiCarlo, F.J., Crew, M.C., Haynes, L.J., Melgar, M.D., Gala, R.L.: The absorption and biotransformation of glyceryl trinitrate-1,3–14C by rats. Biochem. Pharmacol. 17, 2179–2183 (1968).CrossRefGoogle Scholar
  29. DiCarlo, F.J., Crew, M.C., Haynes, L. J., Wilson, M.: Pentaerythritol trinitrate metabolism by the rat. Biochem. Pharmacol. 18, 1985–1990 (1969 a).CrossRefGoogle Scholar
  30. DiCarlo, F.J., Crew, M.C., Sklow, N.J., Coutinko, C.B., Nonkin, P., Simon, F., Bernstein, A.: Metabolism of pentaerythritol tetranitrate by patients with coronary artery disease. J. Pharmacol. exp. Ther. 153, 254–258 (1966).Google Scholar
  31. DiCarlo, F.J., Hartigan, J.M., Coutinko, C.B., Phillips, G.E.: Absorption, distribution and excretion of pentaerythritol and pentaerythritol tetranitrate by mice. Proc. Soc. exp. Biol. (N.Y.) 118, 311–315 (1965 c).Google Scholar
  32. DiCarlo, F.J., Hartigan, J.M., Jr., Phillips, G.E.: Enzymatic degradation of pentaerythritol tetranitrate by human blood. Proc. Soc. exp. Biol. (N.Y.) 118, 514–516 (1965a).Google Scholar
  33. DiCarlo, F.J., Melgar, M.D.: Binding and metabolism of nitroglycerin by rat blood plasma. Proc. Soc. exp. Biol. (N.Y.) 131, 406–408 (1969 c).Google Scholar
  34. DiCarlo, F.J., Melgar, M.D.: Nitroglycerin biotransformation by rat blood serum. Biochem. Pharmacol. 19, 1371–1379(1970).CrossRefGoogle Scholar
  35. DiCarlo, F.J., Melgar, M.D., Haynes, L.J., Gala, R.L., Crew, M.C.: Metabolism of pentaerythritol trinitrate and pentaerythritol by dogs. J. Pharmacol. exp. Ther. 168, 235–239 (1969b).Google Scholar
  36. DiCarlo, F.J., Viau, J., Melgar, M.D.: Incorporation of radioactivity from 14C-nitroglycerin into rat liver glycogen, lipid, protein, ribonucleic acid, and deoxy-ribonucleic acid. Biochem. Pharmacol. 18, 965–970 (1969 d).PubMedCrossRefGoogle Scholar
  37. Dietz, A.J., Jr.: Biotransformation studies on 1-chloro-2,3-propanediol dinitrate. J. Pharm. Sci. 56, 1664–1665 (1967 b).PubMedCrossRefGoogle Scholar
  38. Fouts, J.R., Brodie, B.B.: The enzymatic reduction of chloramphenicol, p-nitrobenzoic acid and other aromatic nitro compounds in mammals. J. Pharmacol. exp. Ther. 119, 197–206 (1956).Google Scholar
  39. Garret, R.H., Nason, A.: Further purification and properties of neurospora nitrate reductase. J. biol. Chem. 244, 2870–2882 (1969).Google Scholar
  40. Goldstein, R.E., Douglas, M.D., Rosing, M.D., Redwood, D.R., Beiser, G.D., Epstein, S.E.: Clinical and circulatory effects of isosorbide dinitrate: comparison with nitroglycerin. Circulation 43, 629–640 (1971).PubMedGoogle Scholar
  41. Grover, P.L., Sims, P.: Conjugations with glutathione. Distribution of glutathione-S-aryltransferase in vertebrate species. Biochem. J. 90, 603–606 (1964).PubMedGoogle Scholar
  42. Hay, M.: The chemical nature and physiological action of nitroglycerin. Practitioner 30, 422–433 (1883).Google Scholar
  43. Heppel, L. A., Hilmoe, R. J.: Metabolism of inorganic nitrite and nitrate esters. II. The enzymatic reduction of nitroglycerin and erythritol tetranitrate by glutathione J. biol. Chem. 183, 129–138 (1950).Google Scholar
  44. Heppel, L.A., Porterfield, V.T.: Metabolism of inorganic nitrite and nitrate esters. I. The coupled oxidation of nitrite by peroxide-forming systems and catalase. J. biol. Chem. 178, 549–556 (1949).PubMedGoogle Scholar
  45. Hunter, F.E., Jr., Ford, L.: Nitrite formation by enzymatic reaction of mannitol hexanitrate with glutathione. J. Pharmacol. exp. Ther. 113, 186–191 (1955).PubMedGoogle Scholar
  46. Hunter, F.E., Jr., Kahana, S., Ford, S.: Effect of inorganic and organic nitrites and nitrates on aerobic phosphorylation in liver mitochondria. Fed. Proc. 12, 221 (1953).Google Scholar
  47. Johnson, E.M., Jr., Harkey, A.B., Blehm, D.J., Needleman, P.: Clearance and metabolism of organic nitrates. J. Pharmacol. exp. Ther. 182, 56–62 (1972).PubMedGoogle Scholar
  48. Johnson, M.K.: A distinct enzyme of rat liver and kidney coupling glutathione with some aliphatic halogen compounds. Biochem. J. 87, 4–9 (1963).Google Scholar
  49. Kohno, K., Noda, K., Mizobe, M., Utsumi, I.: Enzymatic reduction of disulfide-type thiamine derivatives. Biochem. Pharmacol. 18, 1685–1692 (1969).PubMedCrossRefGoogle Scholar
  50. Lang, S., Johnson, E.M., Jr., Needleman, P.: Metabolism of and vascular responses to glyceryl trinitrate in the eviscerated rat. Biochem. Pharmacol. 21, 422–424 (1972).PubMedCrossRefGoogle Scholar
  51. Lee, N.H.: The metabolism of glyceryl trinitrate by liver and blood from different species. Biochem. Pharmacol. 22, 3122–3124 (1973).PubMedCrossRefGoogle Scholar
  52. Lee, N.H., Belpaire, F.M.: Study of the increased glyceryl trinitrate metabolism after pretreatment with phenobarbital in rat liver. Biochem. Pharmacol. 21, 3171–3177 (1972).PubMedCrossRefGoogle Scholar
  53. Lee, N.H., Belpaire, F.M.: Biotransformation of nitroglycerin by organic nitrate reductase. Arch. int. Pharmacodyn. Ther. 196, 165–167 (1972).PubMedGoogle Scholar
  54. Modell, W., (Ed.): Drugs of Choice, 1970–1971, p.376. St. Louis, Mo.: C. V. Mosby Comp. 1970.Google Scholar
  55. Needleman, P., Blehm, D.J., Harkey, A.B., Johnson, E.M., Jr., Lang, S.: The metabolic pathway in the degradation of glyceryl trinitrate. J. Pharmacol. exp. Ther. 179, 347–353 (1971).PubMedGoogle Scholar
  56. Needleman, P., Blehm, D. J., Rotskoff, K.S.: Relationship between glutathione-dependent denization and the vasodilator effectiveness of organic nitrates. J. Pharmacol. exp. Ther. 165, 286–288 (1969).PubMedGoogle Scholar
  57. Needleman, P., Harkey, A.B.: Role of endogenous glutathione in the metabolism of glyceryl trinitrate by isolated perfused rat liver. Biochem. Pharmacol. 20, 1867–1876 (1971 b).PubMedCrossRefGoogle Scholar
  58. Needleman, P., Hunter, F.E., Jr.: The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase. Molec. Pharmacol. 1, 77–86 (1965 a).Google Scholar
  59. Needleman, P., Hunter, F.E., Jr.: Effects of organic nitrates on mitochondrial respiration and swelling: Possible correlations with the mechanism of pharmacologic action. Molec. Pharmacol. 2, 134–143 (1966).Google Scholar
  60. Needleman, P., Krantz, J.C., Jr.: The biotransformation of nitroglycerin. Biochem. Pharmacol. 14, 1225–1230 (1965 b).PubMedCrossRefGoogle Scholar
  61. Needleman, P., Lang, S., Johnson, E.M., Jr.: Organic nitrates: Relationship between biotransformation and rational angina pectoris therapy. J. Pharmacol. exp. Ther. 181, 489–497 (1972).PubMedGoogle Scholar
  62. Oberst, F.W., Snyder, F.H.: Studies on nitrate esters. 1. Nitrite-producing systems in rabbit tissues. J. Pharmacol. exp. Ther. 93, 444–450 (1948).PubMedGoogle Scholar
  63. Omura, H.: Intracellular behavior of the nitrate reductase of animal tissues. Enzymologia 20, 271–290(1959).PubMedGoogle Scholar
  64. Otsuka, S.: Studies on nitro-reducing enzymes of swine liver. Properties and cofactor requirements of nitro- and nitroso reductases. J. Biochem. (Tokyo) 50, 85–94 (1961).Google Scholar
  65. Parker, J.C., Chang, Y., Davidson, I.W.F.: Coronary vasodilator activity of pentaerythritol trinitrate and its metabolites assayed in the dog. Fed. Proc. 32, 794 (1973).Google Scholar
  66. Posadas del Rio, F.: Glutathione organic nitrate ester reductase-evidence for two or more enzymes. Fed. Proc. 29, 412 (1970).Google Scholar
  67. Posadas del Rio, F., Hunter, F.E., Jr.: GSH-organic nitrate ester reductase-purification and properties. Fed. Proc. 32, 733 (1973).Google Scholar
  68. Racker, E.: Glutathione-homocysteine transhydrogenase. J. biol. Chem. 217, 867–874 (1955).PubMedGoogle Scholar
  69. Reed, D.E., May, J.F., Hart, L.G., McCurdy, D.H.: Identification of urinary metabolites of isosorbide dinitrate in dogs. Arch. int. pharmacodyn 191, 318–336 (1971).PubMedGoogle Scholar
  70. Riseman, J. E. F., Altman, G. E., Koretsky, S.: Nitroglycerin and other nitrites in the treatment of angina pectoris. Circulation 17, 22–39 (1958).PubMedGoogle Scholar
  71. Rosseel, M.T., Bogaert, M.G.: Isosorbide, isomannide, and isoidide dinitrate: Urinary excretion in the rat. Biochem. Pharmacol. 22, 67–72 (1973).PubMedCrossRefGoogle Scholar
  72. Rosseel, M.T., Bogaert, M.G.: GLC determination of nitroglycerin and isosorbide dinitrate in human plasma. J. Pharm. Sci. 62, 754–758 (1973).PubMedCrossRefGoogle Scholar
  73. Schelling, J., Lasagna, L.: A study of cross-tolerance to circulatory effects of organic nitrates. Clin. Pharmacol. Ther. 8, 256–260 (1967).PubMedGoogle Scholar
  74. Sherber, D.A., Marcus, M., Kleinberg, S.: Rapid clearance of isosorbide dinitrate from rabbit blood. Determination by gas chromatography. Biochem. Pharmacol. 19, 607–612 (1970).PubMedCrossRefGoogle Scholar
  75. Sisenwine, S.F., Ruelius, H. W.: Plasma concentrations and urinary excretion of isosorbide dinitrate and its metabolites in the dog. J. Pharmacol. exp. Ther. 176, 296–301 (1971).PubMedGoogle Scholar
  76. Tsuruta, H., Hasegawa, H.: Studies on nitroglycol poisoning on some properties of an enzyme which decomposes nitroglycol into inorganic nitrate. Ind. Health 8, 99–118 (1970).CrossRefGoogle Scholar
  77. Wendt, R.L.: Systemic and coronary vascular effects of the 2- and the 5-mononitrate esters of isosorbide. J. Pharmacol. exp. Ther.180, 732–742 (1972).PubMedGoogle Scholar
  78. Yagoda, H., Oettingen, W.F. von: Determination of nitrite in biological fluids and the decomposition of aliphatic nitric esters in vivo and in vitro, Toxicology and Potential Dangers of Pentaerythritol Tetranitrate, Publ. Health Bull. No. 282, 8 (1944).Google Scholar

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  • Philip Needleman

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