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

European Journal of Drug Metabolism and Pharmacokinetics volume 21, pages 315–325 (1996)Cite this 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.

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Affiliations

  1. Groupe de Recherche en Biodynamique du Médicament, Laboratoire de Chimie Analytique et de Spectrométrie de Masse, Faculté de Pharmacie de Clermont-Ferrand, 28 place Henri Dunant, BP 38, 63001, Clermont-Ferrand Cedex, France

    E. Damatte, M. J. Galmier, C. Lartigue-Mattei, N. Busch & J. L. Chabard

  2. RL CERM, Riom, France

    J. F. Pognat

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  1. E. Damatte
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  2. M. J. Galmier
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  3. C. Lartigue-Mattei
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  4. J. F. Pognat
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  5. N. Busch
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  6. J. L. Chabard
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Damatte, E., Galmier, M.J., Lartigue-Mattei, C. et al. Comparative study of the biotransformation of bepridil analogs in isolated liver cells from one rat. Relationships between structure and in vitro liver toxicity. European Journal of Drug Metabolism and Pharmacokinetics 21, 315–325 (1996). https://doi.org/10.1007/BF03189733

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  • DOI: https://doi.org/10.1007/BF03189733

Keywords

  • Bepridril analogs
  • in vitro metabolism
  • liver toxicity