In vitro metabolism of the new anxiolytic agent, RWJ-52763 in human hepatic S9 fraction-API-MS/MS identification of metabolites.
The in vitro metabolism of the anxiolytic agent, RWJ-52763 was studied after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-52763 (64% of the sample) plus six metabolites (M1-M6) were profiled, quantified, and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-52763 are proposed, and the two metabolic pathways are: (1) N/O-dealkylation, and (2) phenylhydroxylation. Pathway 1 formed a major N-dealkylated metabolite, N-desethoxy-RWJ-52763 (M1, 22% of the sample) and 2 minor N/O-dealkylated metabolites, O-desmethyl-RWJ-52763 (M2; 2%) and N,N-didesethoxymethyl-RWJ-52763 (M3; 3%). Pathway 2 produced two hydroxyphenyl metabolites, hydroxydifluorophenyl-RWJ-52763 (M4; 4%) and hydroxyphenyl-pyrido-RWJ-52763 (M5; 3%) in small amounts, and in conjunction with step 1 formed a minor N-desethoxymethyl-M4 (M6; 1%). RWJ-52763 is substantially metabolized by this human hepatic S9.
Wu
Wu-Nan
WN
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh McKean Rds, PO Pox 776, Spring House, PA 19477, USA. wwu@prius.jnj.com
McKown
Linda A
LA
Reitz
Allen B
AB
D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism*; D001711:Biotransformation; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D011728:Pyridones / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*
C476888:6-N,N-dimethoxyethyl-1,2-dihydro-3-oxo-N-(2,6-difluorophenyl)pyrido(1,2-a)benzimidazole-4-carboxamide; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D011728:Pyridones