The Metabolism of a Calcium Entry Blocker, Arylalkylamine Analogue, in the In-Vitro Rat Hepatic System

Abstract

The In vitro metabolism of an arylalkylamine analogue (McN-5691), a calcium entry blocker, was conducted after 0 min and 60 min incubations with the rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged McN-5691 (31% of the sample) plus 15 metabolites from the 60min incubation were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation McN-5691 metabolites are via the following four metabolic pathways: A. N-demethylation, B. O-demethylation, C. phenylhydroxylation, and D. oxidative N-dealkylation. Pathways A to C formed 9 major/moderate/minor metabolites, N-desmethyl (MI, 42% of the sample), 4-O-desmethyl (M2, 6%), 4'-O-desmethyl (M3, 6%), OH-phenyl (M4, 1%), O,O-didesmethyl (M5, 1%), and OH-phenyl-M1 (M6, 1%) McN-5691s, and 3 other minor phenylhydroxyl/N-desmethyl/O-desmethyl-combined McN-5691 metabolites (M7-M9, ≤ 1%). Pathway C produced a N-dealkylated metabolite, M10 (2%); in conjunction with pathways A to C yielded 5 minor oxidized N-dealkylated metabolites M11-M15 (each, ≤ 1-2%). Rat appeared to metabolize McN-5691 extensively in this hepatic system.