In vitro biotransformation of the new antipsychotic agent, RWJ-46344 in rat hepatic S9 fraction: API-MS/MS/MS identification of metabolites.

Abstract

The in vitro biotransformation of the antipsychotic agent, RWJ-46344 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-46344 (approximately 37% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS/MS data. The proposed metabolic pathways for RWJ-46344 are proposed, and the six metabolic pathways are 1, O-dealkylation; 2, piperidinyl oxidation; 3, N-debenzylation; 4, phenyl hydroxylation; 5, dehydration; and 6, reduction. Pathways 1 to 3 formed O-desisopropyl RWJ-46344 (M3, approximately 13% of the sample) and its hydroxy-metabolite (M5, approximately 8%), hydroxypiperidinyl RWJ-46344 (M1, approximately 5%) and a phenylpiperidinyl metabolite (M8, approximately 24%) as major and moderate metabolites. Eight minor metabolites (each < 2%) were formed via a combination of six steps. RWJ-46344 is metabolized substantially by this rat hepatic system.

• Authors: W N Wu, L A McKown, M D Moyer, A B Reitz
• Journal: Journal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 24 Issue 2 Pg. 307-16 (Dec 15 2000) ISSN: 0731-7085 [Print] England
• PMID: 11130209 (Publication Type: Journal Article)

Chemical References

• 4-(2-((1-methylethoxy)phenyl)-1-piperidinyl)methylbenzoyl-2,6-dimethylpiperidine
• Antipsychotic Agents
• Piperidines

Topics

• Animals
• Antipsychotic Agents (pharmacokinetics)
• Biotransformation
• Liver (metabolism)
• Mass Spectrometry (methods)
• Piperidines (pharmacokinetics)
• Rats