Hepatic in Vitro Metabolism of Etoperidone, an Antidepressant Drug, in the Rat and Human

Abstract

The in vitro metabolism of etoperidone (Et), an antidepressant drug, was conducted after 30 and 60 min incubations with rat hepatic S9 fraction, and 60 and 90 min incubations with human hepatic S9 fraction, respectively, in the presence of an NADPH-generating system. Unchanged Et (35% of the sample in rat, 46% in human) plus 8 phase I metabolites from the 60 min rat incubation, and 9 phase I metabolites from the 90 min human incubation, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of Et metaboiltes are via the following three metabolic pathways: 1. alkyl oxidation, 2. phenyl oxidation, and 3. oxidative N-dealkylation, Pathways 1 and 2 formed 2 major metabolites [OH-ethyl Et (M1): 18-21% of the sample; OH-Ph Et (M2): 14-32%] and 3 minor metabolites [oxo-ethyl Et (M3): 1-3%; OH-ethyl-OH-Ph Et (M4): 3-5%; oxo-ethyl-OH-Ph Et (M5): 1-3%] in all species, and pathway 3 in conjunction with phenyl oxidation led to the production of 3 minor metabolites, triazole propyl aldehyde (M6), triazole propionic acid (M7) and OH-Ph-MCPP (M9) with each ≤ 1-2% of the sample, and a moderate metabolite, MCPP (M8, 1-8%) in all species. In general, both rat and human appeared to metabolize Et extensively in this hepatic system.