COMPARATIVE-STUDY OF THE BIOTRANSFORMATION OF BEPRIDIL ANALOGS IN ISOLATED LIVER-CELLS FROM ONE RAT - RELATIONSHIPS BETWEEN STRUCTURE AND IN-VITRO LIVER TOXICITY

The biotransformation of several analogs of the anti-calcium agent bep ridil was studied comparatively in liver cells isolated from one rat. Three types of metabolites were identified by mass spectrometry, resul ting from three phase I reactions: hydroxylation, N-debenzylation and pyrrolidine ring opening. The amount of each bepridil analog untransfo rmed after 18 h of incubation depended on its liver toxicity rather th an on its concentration in the culture medium. The proportion of phase I metabolites identified remained constant regardless of toxicity. Th e difference Delta c (in %) between the initial concentration of the a nalog tested and the sum of the concentrations of untransformed materi al and of identified metabolites decreased with the increasing hepatoc yte toxicity. The analogs tested were responsible for the liver toxici ty. The presence of substituents in different positions on the N-pheny l moiety increased liver toxicity; ortho-substituted analogs were more toxic than para- or meta-substituted ones.