In Vitro Biotransformation of Bepridil, a Calcium Entry Blocker, in the Rat Hepatic System

Abstract

The In vitro biotransformation of bepridil (Bp) (Vascor(superscript ®)), a calcium entry blocker, was conducted after 0 min and 60 min incubations with rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged Bp (14% of the sample) plus 21 metabolites from the 60 min incubation were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of Bp metabolites are via the following eight metabolic pathways: A. phenylhydroxylation, B. alkylhydroxylation, C. pyrrolidyl oxidation, D. dehydration, E. N-debenzylation, F. N-dealkylation, G. O-dealkylation, and H. N-oxidation. Pathways A to D formed 10 mayor/moderate/minor metabolites, OH-phenyl-Bp (M1, 10% of the sample), OH-isobutyl-Bp (M2, 5%), OH-pyrrolidyl-Bp (M3, 4%) and its dehydrated product (M8, 14%), OH-Ph-OH-pyrrolidyl- Bp (M4, 7%), OH-Ph-OH-isobutyl-Bp (M5, 6%), oxo-pyrrolidyl-Bp (M6, 3%), OH-Phoxo-pyrrolidyl-Bp (M7, 2%), triOH-Bp (M9, 3%), and diOH-oxo-Bp (M10, 2%). Pathway E produced N-desbenzyl-Bp (M 11, 2%); in conjunction with pathways A-C formed 4 minor oxidized metabolites of M11, M13, M15-M17 (each, 1-3%). Pathway F formed a minor N-desisobutyl-Bp (MI2, 4%); in conjunction with pathways A and C produced 4 moderate/minor/trace oxidized metabolites of M12 (4%), M14 (6%) and M18-M20 (each, ＜1-4%). Pathway H produced Bp-Noxide (3%) as an artifact. In general, rat appeared to metabolize Bp extensively in this hepatic system.