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

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 24; no. 2; pp. 307 - 316
• Main Authors: Wu, Wu-Nan, McKown, Linda A, Moyer, Michael D, Reitz, Allen B
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.12.2000; Elsevier Science
• Subjects: Analysis; Animals; Antipsychotic agent; Antipsychotic Agents - pharmacokinetics; API-MS/MS/MS; Biological and medical sciences; Biotransformation; General pharmacology; In vitro metabolism; Liver - metabolism; Mass Spectrometry - methods; mass spectroscopy; Medical sciences; Pharmacology. Drug treatments; Piperidines - pharmacokinetics; Rat hepatic S9; Rats; RWJ-46344; In vitro metabolism; Rat hepatic S9; API-MS/MS/MS; Antipsychotic agent; RWJ-46344; Rat; Digestive system; Metabolite; Liver; Ion beam sputtering; Rodentia; HPLC chromatography; Metabolism; In vitro; Vertebrata; Mammalia; Animal; Mass spectrometry MS/MS; Antipsychotic; Quantitative analysis
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/S0731-7085(00)00421-0

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 (∼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,∼13% of the sample) and its hydroxy-metabolite (M5,∼8%), hydroxy-piperidinyl RWJ-46344 (M1,∼5%) and a phenylpiperidinyl metabolite (M8,∼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.