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Isolation and characterization of the urinary metabolites of arbaprostil in the male dog after intravenous administration

  • Bruce A. Thornburgh
  • S. Robert Shaw
  • George E. Bronson
  • Asoka J. Wickrema Sinha
Original papers

Summary

The profile of urinary metabolites of3H-arbaprostil was characterized in the male dog after intravenous administration. The major metabolites were purified and their structures deduced by gas chromatography/mass spectrometry (GC/MS) studies after conversion to the methyl ester-methoxime-trimethylsilyl ether derivatives, aided by GC with simultaneous radioactivity monitoring. The identified metabolites accounted for 96% of the urinary excretion products. β-Oxidation of the carboxy side-chain of arbaprostil to 15-methyl-2,3,4,5-tetranor PGE1, via the 15-methyl-2,3-dinor PGE: intermediate, appeared to be the most significant metabolic pathway. In contrast to the rat. the following were observed in the dog: glucuronic acid conjugation of the 15-methyl-2,3,4,5-tetranor PGE, and PGA metabolites; detection of the l5-methyl-2,3-dinor PGE2 intermediate; absence of 19-hydroxyl-15-methyl-2,3.4,5.-tetranor PGA. and PGB metabolites; oxidation at C-20; and excretion of some parent drug.

Keywords

Arbaprostil 15(R)-15-methyl prostaglandin dog 

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References

  1. 1.
    Robert A. Kane G. Reele S. (1981): Dose response inhibition in man of meal-stimulated gastric acid secretion by I5(R)-15methyl prostaglandin E2, given orally. Gut. 22. 728–731.CrossRefPubMedGoogle Scholar
  2. 2.
    Konturek S.S., Kweicien N., Swierczek J., Oleksy J., Sito H. and Robert A. (1976): Comparison of methylated prostaglandin E2 analogues given orally in the inhibition of gastric responses to pentagastrin and peptone meal in man. Gastroenterology. 70, 683–687.PubMedGoogle Scholar
  3. 3.
    Robed A., Schultz J.R., Nezamis J.E., Lancaster C. (1976): Gastric antisecretory and antiulcer properties of PGE2, 15-methyl PGE2, and 16.16-dimethyl PGE2, Intravenous, oral and intrajejunal administration. Gastroenterology. 70. 359–370.Google Scholar
  4. 4.
    Kollberg B., Johansson C. (1979): The inhibitory effect of 15(R)15-methyl prostaglandin E2 and the interaction with atropine on stimulated gastric acid secretion in man. Scand. J. Gastroenterol., 14. 337–342.CrossRefPubMedGoogle Scholar
  5. 5.
    Peterson W., Feldman M., Taylor I., Bremer M. (1979): The effect of 15(R)-15-methyl prostaglandin E2 on meal-stimulated gastric acid secretion, serum gastrin, and pancreatic polypeptide in duodenal ulcer patients. Dig. Dis. Sci., 24.381–384.CrossRefPubMedGoogle Scholar
  6. 6.
    Gilbert D.A., Feld A.D., Silverstein F.E., Weinberg C. Sauders D.R. (1981): I5(R)-15-methyl prostaglandin E2 (PGE2) cytoprotection in aspirin-induced gastric mucosal injury — an endoscopic study. Gastroenterology. 80. 1155.Google Scholar
  7. 7.
    Kolberg B., Nordemar R., Johansson C. (1981): Gastrointestinal protection by low-dose oral prostaglandin E2 in rheumatic diseases. Scand. J. Gastroenterol., 16. 1005–1008.CrossRefGoogle Scholar
  8. 8.
    Vantrappen G., Janssens J., Popiela T., Kulig J., Tytgat G.N.J., Huibregtse K., Lambert R., Pauchard J.P., Robert A. (1982): Effect of l5(R)-15-methyl prostaglandin E2 (arbaprostil) on the healing of duodenal ulcer: A double-blind multicenter study. Gastroenterology. 83. 357–363.PubMedGoogle Scholar
  9. 9.
    dWickrema Sinha A.J., Shaw S.R., Thornburgh B.A. (1985): Absorption, tissue distribution and excretion of3H-labelled Arbaprostil in the rat. Eur. J. Drug Metab. Pharmacokin., 10. 171–177.CrossRefGoogle Scholar
  10. 10.
    Thornburgh B.A., Shaw.S.R., Wickrema Sinha A.J. (1986): Isolation and characterization of urinary metabolites of arbaprostil in the rat. Eur. J.Drug Metab. Pharmacokin., 11. 61–69.CrossRefGoogle Scholar
  11. 11.
    Hsi R.S.P., Yankee E.W., Stolle W.T. (1987): Synthesis of tritium labelled Arbaprostil and its C-15 epimer. American Nuclear Society 1987 Winter Meeting. November 15–19. Los Angeles. CA. USAGoogle Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • Bruce A. Thornburgh
    • 1
  • S. Robert Shaw
    • 1
  • George E. Bronson
    • 1
  • Asoka J. Wickrema Sinha
    • 1
  1. 1.Drug Metabolism ResearchThe Upjohn CompanyKalamazooUSA

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