Induction of drug metabolism in the rat by taglutimide, a sedative-hypnotic glutarimide derivative

  • Hubert Wiener
  • Peter Krivanek
  • Elisabeth Tuisl
  • Norbert Kolassa
Original Papers


Pretreatment with taglutimide significantly decreased the plasma dicoumarol level and shortened the duration of hexobarbital-induced narcosis in rats. Furthermore, taglutimide pretreatment accelerated thein vitro metabolism of dicoumarol, hexobarbital, o-nitrophenyl acetate and procaine, but not of 3,4-benzpyrene, as assayed in the 10,000xg supernatant fraction of rat liver homogenate. No definite increase was observed in liver wet weight, nor in the amount of microsomal and total liver protein in comparison with the control values. No marked differences were found between the effects of short-(4-day) and long-term (17-day) pretreatment on any of the studied parameters. The changes in drug metabolism and liver protein observed after taglutimide pretreatment differed from those observed after pretreatment with either phenobarbital or 3,4-benzpyrene. Taglutimide, like other inducing agents, is lipophilic, but differs from them in not being a substrate of monooxygenases.


Drug metabolism Induction Glutarimide derivatives Taglutimide Rat 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Koehler F. and Koch H. (1974): Teratologische Untersuchungen der Thalidomid-aehnlichen Verbindungen K-2004 und K-2604 an Maus und Ratte. Arzneim.-Forsch.,24, 1616–1619.Google Scholar
  2. 2.
    Argyropoulos G., Lanner G. and Pasquali E. (1976): Klinische und elektroenzephalographische Studien mit einem neuen Hypnosedativum K-2004. Wien. Med. Wschr.,126, 75–77.PubMedGoogle Scholar
  3. 3.
    Schuetzenberger W.G., Kolassa N., Wiener H., Kraupp O., and Tuisl E. (1979): Pharmacological properties of biglumide, a new sedative hypnotic drug. Arzneim.-Forsch.,29, 1146–1150.Google Scholar
  4. 4.
    Remmer H. (1962): in “Symp. Redoxfunktionen Cytoplasmatischer Strukturen”, Gemeinsame Tagung Dtsch. Ges. Physiol. Chem. und Oesterr. Biochem. Ges. in Wien, p. 75.Google Scholar
  5. 5.
    Kato R., Chiesara E. and Vassanelli P. (1964): Further studies on the inhibition and stimulation of microsomal drug-metabolizing enzymes of rat liver by various compounds. Biochem. Pharmac.,13, 69–83.CrossRefGoogle Scholar
  6. 6.
    Conney A.H. (1967): Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev.19, 317–366.PubMedGoogle Scholar
  7. 7.
    Hunter J. and Chasseaud L.F. (1976): Clinical aspects of microsomal enzyme induction. In “Progress in Drug Metabolism” (J.W. Bridges and L.F. Chasseaud, eds.), Vol. 1, p. 129–191. John Wiley & Sons, London.Google Scholar
  8. 8.
    Zaroslinski J., Browne R. and Possley L. (1972): Effect of subacute administration of methaqualone, phenobarbital and glutethimide on plasma levels of bishydroxycoumarin. Arch. int. Pharmacodyn.,195, 185–191.PubMedGoogle Scholar
  9. 9.
    Axelrod J., Cooper J.R. and Brodie B.B. (1949): Estimation of dicumarol, 3,3-methylenebis(4-hydroxycoumarin) in biological fluids. Proc. Soc. Exp. Biol. Med.,70, 693–695.PubMedGoogle Scholar
  10. 10.
    Conney A.H., Davison C., Gastel R. and Burns J.J. (1960): Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J. Pharmacol. Exp. Ther.,130, 1–8.PubMedGoogle Scholar
  11. 11.
    Mazel P. (1971): Experiments illustrating drug metabolism in vitro. In “Fundamentals of Drug Metabolism and Drug Disposition” (B.N. La Du, H.G. Mandel and E.L. Way, eds.), p. 546–582, Williams & Wilkins Co., Baltimore.Google Scholar
  12. 12.
    Layne E. (1957). Spectrophotometric and turbidimetric methods for measuring proteins. In “Methods in Enzymology” (S.P. Colowick and N.O. Kaplan, eds.), Vol. 3, p. 447–454, Academic Press, New York.Google Scholar
  13. 13.
    Cooper J.R. and Brodie B.B. (1955): The enzymatic metabolism of hexobarbital (evipal). J. Pharmacol. Exp. Ther.,114, 409–417.PubMedGoogle Scholar
  14. 14.
    Remmer H. and Merker H.J. (1963): Drug-induced changes in the liver endoplasmic reticulum: Association with drug-metabolizing enzymes. Science,142, 1657–1658.CrossRefPubMedGoogle Scholar
  15. 15.
    Conney A.H., Miller E.C. and Miller J.A. (1957): Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J. Biol. Chem.,228, 753–766.PubMedGoogle Scholar
  16. 16.
    Krisch K. (1966): Reaction of a microsomal esterase from hog-liver with diethyl p-nitrophenyl phosphate. Biochim. Biophys. Acta.,122, 265–280.PubMedGoogle Scholar
  17. 17.
    Koch-Weser J. and Sellers E.M. (1971): Drug interactions with coumarin anticoagulants. I. New. Engl. J. Med.,285, 487–498.CrossRefGoogle Scholar
  18. 18.
    Barker W.M., Hermodson M.A. and Link K.P. (1970): The metabolism of 4-C14-warfarin sodium by the rat. J. Pharmacol. Exp. Ther.,171, 307–313.PubMedGoogle Scholar
  19. 19.
    Kaighen M. and Williams R.T. (1961): Metabolism of coumarin-3-C14. J. med. pharm. Chem.,3, 25–43.CrossRefGoogle Scholar
  20. 20.
    Pischek G., Kaiser E. and Koch H. (1974): Thalidomid-Analoga, 5. Mitt.: Untersuchungen zum Metabolismus der Thalidomid-aehnlichen Verbindung K-2004. Monatsh. Chem.,105, 74–79.CrossRefGoogle Scholar
  21. 21.
    Pischek G. and Koch H. (1976): Thalidomid-Analoga, 7. Mitt.: Metabolisierung und Elimination der Thalidomidaehnlichen Verbindungen K-2004 bei der Ratte. Arch. Pharm.,309, 62–69.CrossRefGoogle Scholar
  22. 22.
    Aggeler P.M. and O’Reilly R.A. (1969): Effect of heptabarbital on the response to bishydroxycoumarin in man. J. Lab. Clin. Med.,74, 229–238.PubMedGoogle Scholar
  23. 23.
    Conney A.H. (1971): Environmental factors influencing drug metabolism. In “Fundamentals of Drug Metabolism and Drug Disposition” (B.N. La Du, H.G. Mandel and E.L. Way, eds.), p. 253–278, Williams & Wilkins Co., Baltimore.Google Scholar
  24. 24.
    Breckenridge A., Orme M.L’E., Davies L., Thorgeirsson S.S. and Davies D.S. (1973): Dose-dependent enzyme induction. Clin. Pharmacol. Ther.,14, 514–520.PubMedGoogle Scholar
  25. 25.
    Moroi K. and Satoh T. (1975): Modification of procaine metabolism in rat liver after administration of phenobarbital or ethyl p-nitrophenyl phenylphosphonothioate. Biochem. Pharmac.,24, 1436–1438.CrossRefGoogle Scholar
  26. 26.
    Gram T.E. and Gillette J.R. (1971): Biotransformation of drugs. In “Fundamentals of Biochemical Pharmacology” (Z.M. Bacq, ed.), p. 571–609, Pergamon Press, Oxford.Google Scholar
  27. 27.
    Goldschmidt S. and Wehr R. (1957): Ueber Barbiturate, III. Mitteilung. Der Metabolismus von Veronal. Hoppe-Seyler’s Z. Physiol. Chem.,308, 9–19.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • Hubert Wiener
    • 1
  • Peter Krivanek
    • 1
  • Elisabeth Tuisl
    • 1
  • Norbert Kolassa
    • 1
  1. 1.Institute of PharmacologyUniversity of ViennaViennaAustria

Personalised recommendations