Advertisement

Metabolism of Nitroimidazoles

  • D. E. Schwartz
  • W. Hofheinz
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 42)

Abstract

The development in recent years of nitroimidazoles as chemotherapeutic agents has been extensive. The interest in this class of compounds apparently was raised in 1955 by the elucidation of the structure of the antibiotic Azomycin by Nakamura(l) and the discovery of the in vivo activity of 5-nitro-imidazoles against Trichomonas vaginalis(2). Since then an ever growing number of 2- and 5-nitro-imidazoles have been synthesized.

Keywords

Nitro Group Chinese Hamster Ovary Cell Imidazole Ring Aromatic Nitro Compound Unidentified Metabolite 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    S. Nakamura, Structure of azomycin, a new antibiotic, Pharm. Bull. Japan 3: 379 (1955).Google Scholar
  2. 2.
    C. Cosar and L. Julou, Activité de (hydroxy-2’-éthyl)-1-méthyl-2-nitro-5-imidazole (8.823 RP) vis-à-vis des infections expérimentales à Trichomonas vaginalis, Ann.Inst.Pasteur 96: 238 (1959).Google Scholar
  3. 3.
    G.L. Law, G.P. Mansfield, D.F. Muggleton and E.W. Parnell, Dimetridazole: Absorption, excretion and metabolism in turkeys, Nature (Lond.) 197: 1024 (1963).CrossRefGoogle Scholar
  4. 4.
    H.B. Condren, R.E. Davies, C.W. Deyoe, C.R. Creger and J.R. Couch, Effects of 1,2-dimethyl-5-nitroimidazole on growth and reproduction in turkeys and its residual concentration in tissues, Poultry Sci. 41: 1637 (1962)Google Scholar
  5. 5.
    J.E. Stambaugh, L.G. Feo and R.W. Manthei, The isolation and identification of the urinary metabolites of metronidazole in man, J. PharmaсоI.Exp.Ther. 161: 373 (1968).Google Scholar
  6. 6.
    R.M.J. Ings, J.A. McFadzean and W.E. Ormerod, The fate of metronidazole and it implications in chemotherapy, Xenobiotica 5: 223 (1975).PubMedCrossRefGoogle Scholar
  7. 7.
    R.L. Koch and P. Goldman, The anaerobic metabolism of metronidazole forms N-(2-hydroxyethyl)-oxamic acid, J. Pharmacol. Exp.Ther. 208: 406 (1978).Google Scholar
  8. 8.
    R.L. Koch, E.J.T. Chrystal, B.B. Beaulieu Jr. and P. Goldman, Acetamida - a metabolite of metronidazole formed by the intestinal flora, Biochem. Pharmacol. 28: 3611 (1979).Google Scholar
  9. 9.
    C. Rosenblum, N.R. Trenner and D.E. Wolf, The non-metabolite residue - a limitation to the tracer method, J. Labelled Compounds 7: 225 (1970).CrossRefGoogle Scholar
  10. 10.
    C. Rosenblum, N.R. Trenner, R.P. Buhs, C.B. Hiremath, F.R. Koniuszy and D.E. Wolf, Metabolism of ronidazole (l-methyl-5-nitroimidazole-2-ylmethyl carbamate), J.Agr. Food Chem. 20: 360 (1972).CrossRefGoogle Scholar
  11. 11.
    R.P. Buhs, A. Rosegay, T.A. Jacob, N. Allen and F.J. Wolf, Reduction of ronidazole (l-methyl-2-carbamoyl-oxymethyl-5- nitroimidazole) in vivo, Pharmacologist 21:232 Abstract No. 462 (1979).Google Scholar
  12. 12.
    F.J. Wolf, T.A. Jacob, J.J. Steffen, R.F. Alvaro, M.L. Green, L.R. Chapin and R.L. Ellsworth, Ronidazole - The contributions of reductive metabolism in the formation of tissue residues, Pharmacologist 21:232, Abstract No. 461 (1979).Google Scholar
  13. 13.
    B.A. Wood, D. Rycroft and A.M. Monro, The metabolism of tinidazole in the rat and dog, Xenobiotica 3: 801 (1973).PubMedCrossRefGoogle Scholar
  14. 14.
    D.E. Schwartz, J-C. Jordan, W. Vetter and G. Oesterhelt, Metabolic studies of ornidazole in the rat, in the dog and in man, Xenobiotica 9: 571 (1979).Google Scholar
  15. 15.
    R. Richie, H.J. Scholer, P. Angehrn, M. Fernex, H. Hummler, F. Jeunet, K. Schârer, M. Schttpbach and D.E. Schwartz, Grundlagen der Chemotherapie von Trichomoniasis und Amoebiasis mit Ornidazol, Arzneim.-Forsch. (Drug Res) 28: 612 (1978).Google Scholar
  16. 16.
    A.G. Zacchei, L. Zahniser, W.P. Freeborn and F.G. McMahon, Excretion and metabolism of 1-(2-hydroxyethyl)-2-(p- fluorophenyl)-5-nitroimidazole- 2l4C in rat, dog and human, Fed. Proc. 29:2430 (1970).Google Scholar
  17. 17.
    J. Fellig, A. MacDonald, E. Meseck and H. Laurencot, The metabolism of ipronidazole in the turkey, Poultry Sci. 48: 1806 (1969).Google Scholar
  18. 18.
    A. MacDonald, G. Chen, M. Kaykaty and J. Fellig, Residue analysis of ipronidazole and its metabolite at the 2 ppb level in turkey tissue, J.Agr. Food Chem. 19: 1222 (1971).CrossRefGoogle Scholar
  19. 19.
    J. Fellig, M. Kaykaty, L. Gonzales, H.G. Eisenbeis and R.E. Messersmith, Elimination of ipronidazole from the tissues of swine, Vet. Med. 70: 31 (1975).Google Scholar
  20. 20.
    G. Weiss, N. Rose and P. Duke, Submitted to Xenobiotica.Google Scholar
  21. 21.
    P.N. Giraldi, G.P. Tosolini, E. Dradi, G. Nannini, R. Longo, G. Meinardi, G. Monti and I. Deearneri, Isolation identification and quantitative determination in humans of the metabolites of a new trichomonicidal agent (nimorazole), Biochem. Pharmacol. 20: 339 (1971).Google Scholar
  22. 22.
    I.R. Flockhart, P. Large, D. Troup, S.L. Malcolm and T.R.Marten, Pharmacokinetic and metabolic studies of the hypoxic cell radiosensitizer misonidazole, Xenobiotica 8: 97 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    D.E. Schwartz, J-C. Jordan, W. Vetter and G. Oesterhelt, Unpublished results.Google Scholar
  24. 24.
    L.F. Zerilli, N. Rimorini, M. Landi, B. Cavalleri and A. Assandri, GC and MS in the identification of metabolites of 5-(1-methylethy1)-l-methyl-2-nitro-lH-imidazole in dogs, in: “Recent Developments in Mass Spectroscopy in Biochemistry and Medicine”, A. Frigerio, ed., Plenum Publishing Corp., New York (1978).Google Scholar
  25. 25.
    A. Assandri, A. Perazzi, L.F. Zerilli, P. Ferrari and E. Martinelli, Metabolism of 5-isopropyl-l-methyl-2-nitro- lH-imidazole. Identification of some urinary metabolites in the dog, Drug Metab. Dispos. 6: 109 (1978).Google Scholar
  26. 26.
    B. Cavalleri, G. Volpe, V. Arioli and G. Lancini, Synthesis and biological activity of two metabolites of l-methy-5-(1- methylethyl)-2-nitro-lH-imidazole, an antiprotozoal agent, J. Med. Chem. 20: 1522 (1977).PubMedCrossRefGoogle Scholar
  27. 27.
    B. Testa and P. Jenner, Drug metabolism: Reduction of the nitrogen-containing functional groups, in: “Drugs and the Pharmaceutical Sciences” J. Swarbrick, ed., Vol. 4, Marcel Dekker, New York and Basle (1976).Google Scholar
  28. 28.
    M. Mitchard, Bioreduction of organic nitrogen, Xenobiotica 1: 469 (1971).PubMedCrossRefGoogle Scholar
  29. 29.
    J.R. Fouts and B.B. Brodie, The enzymatic reduction of chloramphenicol, p-nitrobenzoic acid and other aromatic nitro compounds in mammals, J.Pharmacol.Exp.Ther. 119: 197 (1957).PubMedGoogle Scholar
  30. 30.
    I. Bartosek, E. Mussini, C. Saronio and S. Garattini, Studies on nitrazepam reduction in vitro, Europ. J. Pharmacol. 11: 249 (1970).Google Scholar
  31. 31.
    J.R. Gillette, J.J. Kamm and H.A. Sasame, Mechanism of p-nitrobenzoate reduction in liver: The possible role of cytochrome P-450 in liver microsomes. Mol.Pharmacol. 4: 541 (1968).PubMedGoogle Scholar
  32. 32.
    R.T. Williams, “Detoxification Mechanisms”. Chapman and Hall London (1959).Google Scholar
  33. 33.
    J. Reider and G. Wendt, Pharmacokinetics and metabolism of the hypnotic nitrazepam, in: “The Benzodiazepines”, S. Garattini, E. Mussini and L.O. Randall, eds., Raven Press, New York (1973).Google Scholar
  34. 34.
    E. Eschenhof, Untersuchungen liber das Schicksal des Anti-konvulsivums Clonazepam im Organismus der Ratte, des Hundes und des Menschen. Arzneim.-Forsch. (Drug Res) 23: 390 (1973).Google Scholar
  35. 35.
    K.M. Baker, M. Coerezza, L. Del Corona, A. Frigerio, G.G. Massaroli and G. Sekules, Metabolism of l-methyl-5-nitro- 2-(21-pyrimidyl)imidazole, J.Pharmac.Sci. 63: 293 (1974).CrossRefGoogle Scholar
  36. 36.
    R.G. Fargher, Orientation of the nitro- and arylazo-glyoxalines. Fission of the glyoxalone nucleus, J.Chem. Soc. 117: 668 (1920).CrossRefGoogle Scholar
  37. 37.
    F.L. Pyman, Orientation of the 1-4 and 1-5 dimethylglyoxalines. Mode of fission of the 5-aminoglyoxalines, J. Chem. Soc. 121: 2616 (1922).CrossRefGoogle Scholar
  38. 38.
    R. Weidenhagen and R. Herrmann, Ueber das 4(5)-Amino-5(4)-methyl-imidazol, Berichte 68: 2205 (1935).Google Scholar
  39. 39.
    M.A. Schwartz and M.K. Taylor (personal communication).Google Scholar
  40. 40.
    Y.C. Taylor and A.M. Rauth, Differences in the toxicity and metabolism of the 2-nitroimidazole misonidazole (Ro 7-0582) in HeLa and Chinese hamster ovary cells, Cancer Res. 38: 2745 (1978).PubMedGoogle Scholar
  41. 41.
    P. Mazel, Determination of microsomal azo and nitro-reductase activities. in: “Fundamentals of Drug Metabolism and Drug Disposition”, B.N. La Du, H.G. Mandel and E.L. May, eds., Williams and Wilkins, Baltimore (1972).Google Scholar
  42. 42.
    P. Populaire, F. Benazet, S. Pascal, G. Lebreton, B. Decouvelaere and L. Guillaume, Circulation et sort du metronidazole dans le tractus digestif chez le rat après administration par voie orale. Absorption due metronidazole par les muqueuses digestives. Thérapie 26: 581 (1971).PubMedGoogle Scholar
  43. 43.
    R.R. Scheline, Metabolism of foreign compounds by gastrointestinal microorganisms, Pharmacol. Reviews 25: 451 (1973).Google Scholar
  44. 44.
    A.J.F. Searle and R.L. Willson, Metronidazole (FLAGYL): Degradation by the intestinal flora, Xenobiotica 6: 457 (1976).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • D. E. Schwartz
    • 1
  • W. Hofheinz
    • 1
  1. 1.Research DepartmentsF. Hoffmann-La Roche & Co.Ltd.BasleSwitzerland

Personalised recommendations