Metabolism of the New Anxiolytic Agent, a Pyrido [1,2α] Benzimidazole (PBI) Analog (RWJ-51204): Identification of Cytochrome P450 Isoforms Mediated in the Human Microsomal Metabolism

The in vitro metabolism of pyrido [1,2α] benzimidazole (PBI) analog (RWJ-51204), an anxiolytic agent, was investigated after incubation with human microsomes and 7 human microsomes containing individual human cytochrome P450 (CYP) isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, in the presence of NADPH-generating system. Unchanged RWJ-51204 (99.8-85.9% of the sample) plus 2 phenolic metabolites (M1 and M2) were profiled, quantified and tentatively identified based on the LC/API-MS and MS/MS data. The formation of RWJ-51204 metabolites are via 2 phenylhydroxylation pathways, which formed 4-hydroxyphenyl-RWJ-51204 (M1, 0.2-9.5%) and hydroxy-benzimidazole-RWJ-51204 (M2, 0.1-4.6%). CYP2D6 and CYP3A4 are mainly responsible for the formation of two oxidized metabolites, M1 and M2.