Advertisement

Comparative study of the biotransformation of bepridil analogs in isolated liver cells from one rat. Relationships between structure and in vitro liver toxicity

  • E. Damatte
  • M. J. Galmier
  • C. Lartigue-Mattei
  • J. F. Pognat
  • N. Busch
  • J. L. Chabard
Article

Summary

The biotransformation of several analogs of the anti-calcium agent bepridil was studied comparatively in liver cells isolated from one rat. Three types of metabolites were identified by mass spectrometry, resulting from three phase I reactions: hydroxylation, N-debenzylation and pyrrolidine ring opening. The amount of each bepridil analog untransformed after 18 h of incubation depended on its liver toxicity rather than on its concentration in the culture medium. The proportion of phase I metabolites identified remained constant regardless of toxicity. The difference Δc (in %) between the initial concentration of the analog tested and the sum of the concentrations of untransformed material and of identified metabolites decreased with the increasing hepatocyte toxicity. The analogs tested were responsible for the liver toxicity. The presence of substituents in different positions on the N-phenyl moiety increased liver toxicity;ortho-substituted analogs were more toxic thanpara- ormeta-substituted ones.

Keywords

Bepridril analogs in vitro metabolism liver toxicity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Billings R., McMahon R.E., Ashmore J., Wagle S.R. (1977): The metabolism of drugs in isolated rat hepatocytes. A comparison with in vitro drug metabolism and drug metabolism in subcellular liver fractions. Drug Metab. Dispos., 5, 518–526.PubMedGoogle Scholar
  2. 2.
    Stammati A.P., Silano V., Zucco F. (1981): Toxicology investigation with cell culture systems. Toxicology, 20, 91–153.CrossRefPubMedGoogle Scholar
  3. 3.
    Lavrijsen K., Van Houdt J., Van Dyck D., Hendrickx J. et al. (1992): Comparative metabolism of flunarizine in rats, dogs and man: an in vitro study with subcellular liver fractions and isolated hepatocytes. Xenobiotica, 22, 815–836.CrossRefPubMedGoogle Scholar
  4. 4.
    Bridges J.W., Benford D.J., Hubbard S.A. (1983): Mechanisms of toxic cell injury. Ann. NY Acad. Sci., 407, 42–63.CrossRefPubMedGoogle Scholar
  5. 5.
    Guillouzo A., Begue J.M., Campion J.P., Gascoin M.N., Guguen-Guillouzo C. (1985): Human hepatocyte cultures: a model of pharmaco-toxicological studies. Xenobiotica, 15, 635–641.CrossRefPubMedGoogle Scholar
  6. 6.
    Sherratt A.J., Damani L.A. (1989): Activities of cytosolic and microsomal drug oxidases of rat hepatocytes in primary culture. Drug Metab. Dispos., 17, 20–25.PubMedGoogle Scholar
  7. 7.
    Guzelian P.S., Montgomery A., Bissel M., Meyer U.A. (1977): Drug metabolism in adult rat hepatocytes in primary monolayer culture. Gastroenterology, 72, 1232–1239.PubMedGoogle Scholar
  8. 8.
    Dougherty K., Spilman S.D., Green C.E., Steward A.R., Byard J.L. (1980): Primary culture of adult mouse and rat hepatocytes for studying the metabolism of foreign chemicals. Biochem. Pharmacol., 29, 2117–2124.CrossRefPubMedGoogle Scholar
  9. 9.
    Rogiers V., Vandenberghe A., Callaerts A., Sonck W., Vercruysse A. (1990): Effects of dimethylsulfoxide on phase I and II biotransformation in cultured rat hepatocytes. Toxicity In Vitro, 4, 439–442.CrossRefGoogle Scholar
  10. 10.
    Moldeus P., Hogberg J., Orrenius S. (1978): Microsomal electron transport and cyt P-450. (4) Isolation and use of liver cells. Methods Enzymol., 52, 60–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Shrivastava R., John G.W., Rispat G., Chevalier A., Massinhham R. (1991): Can the in vivo maximum tolerated dose be predicted using in vitro techniques? A working hypothesis, ALTA, 19, 393–402.Google Scholar
  12. 12.
    Wu W.N., Hills J.F., Chang S.Y., Ng K.T. (1987): Metabolism of bepridil in laboratory animals and humans. Drug Metab. Dispos., 16, 69–77.Google Scholar
  13. 13.
    Gillette J.R. (1979): Effects of induction of cytochrome P-450 enzymes on the concentration of foreign compounds and their metabolites and on the toxicological effects of these compounds. Drug Metab. Rev. 10, 59–87.CrossRefPubMedGoogle Scholar
  14. 14.
    Maslansky C.J., Williams G.M. (1982): Primary cultures and the levels of cytochrome P-450 in hepatocytes from mouse, rat, hamster and rabbit liver. In Vitro, 18, 683–693.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • E. Damatte
    • 1
  • M. J. Galmier
    • 1
  • C. Lartigue-Mattei
    • 1
  • J. F. Pognat
    • 2
  • N. Busch
    • 1
  • J. L. Chabard
    • 1
  1. 1.Groupe de Recherche en Biodynamique du Médicament, Laboratoire de Chimie Analytique et de Spectrométrie de MasseFaculté de Pharmacie de Clermont-FerrandClermont-Ferrand CedexFrance
  2. 2.RL CERMRiomFrance

Personalised recommendations