title: In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp.
abstract: The in-vitro biotransformation of the anxiolytic agent, RWJ-50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system, and incubating with Cunninghamella echinulata in soy-bean medium. Unchanged RWJ-50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1-M6) were profiled, quantified and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-50172 are proposed, and the four metabolic pathways are: pyrido-oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy-pyrido-RWJ-50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro-RWJ-50172 in trace quantities in rat. Pathway B produced hydroxyphenyl-RWJ-50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy-RWJ-50172 as a trace metabolite in rat. Step D produced a minor benzimidazole-reduced metabolite in fungi. RWJ-50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA. wwu@prdus.jnj.com
authors.forename: Wu-Nan
authors.initials: WN
authors.lastname: Wu
authors.forename: Linda A
authors.initials: LA
authors.lastname: McKown
authors.forename: John L
authors.initials: JL
authors.lastname: Melton
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D000577:Amides / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D020093:Cunninghamella / Q000201:enzymology / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C479871:7-fluoro-1,2-dihydro-3-oxo-N-(2,6-diflurophenyl)pyrido(1,2-alpha)benzimidazole-4-carboxamide; D000577:Amides; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles