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: Wu-Nan Wu, Linda A McKown, John L Melton, Allen B Reitz
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 55 Issue 8 Pg. 1099-105 (Aug 2003) ISSN: 0022-3573 [Print] England
• PMID: 12956899 (Publication Type: Journal Article)

Chemical References

• 7-fluoro-1,2-dihydro-3-oxo-N-(2,6-diflurophenyl)pyrido(1,2-alpha)benzimidazole-4-carboxamide
• Amides
• Anti-Anxiety Agents
• Benzimidazoles

Topics

• Amides (metabolism, pharmacokinetics)
• Animals
• Anti-Anxiety Agents (metabolism, pharmacokinetics)
• Benzimidazoles (metabolism, pharmacokinetics)
• Biotransformation
• Cunninghamella (enzymology, metabolism)
• In Vitro Techniques
• Male
• Microsomes, Liver (metabolism)
• Rats
• Rats, Sprague-Dawley