Document Detail


Biosynthesis and identification of an N-oxide/N-glucuronide metabolite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004.
MedLine Citation:
PMID:  21896789     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This article describes the biosynthesis and identification of a new class of metabolites, a piperazine N-oxide/N-glucuronide metabolite 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-1-β-D-glucuronic acid-piperazine 1-oxide (4). The metabolite was found in urine and plasma from humans and animals dosed with 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (Lu AA21004, 1), as a novel multimodal antidepressant under development for treatment of depression. Human liver microsomes in combination with uridine 5'-diphosphoglucuronic acid were used as an in vitro system to generate enough material of 4 to perform one- and two-dimensional (1)H and (13)C NMR experiments for structure elucidation. Based on rotating frame Overhauser enhancement spectroscopy NMR experiments, the distance correlation between a piperazine proton and the anomeric proton of the glucuronic acid moiety is of a magnitude similar to that of the H-3' and H-5' protons and can only be explained by proximity in space and the postulated structure (4). The structural analog, the N-O-glucuronic acid conjugate 6-{4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-yloxy}-1-β-D-glucuronic acid (3) was also observed in biological samples from humans and animals and the first organic synthesis and structural identification of this metabolite is also reported. Treatment of the glucuronide metabolites 3 and 4 with β-glucuronidase gave mainly the expected hydrolysis product, the hydroxyl amine 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-ol (2).
Authors:
Henriette Kold Uldam; Martin Juhl; Henrik Pedersen; Lars Dalgaard
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Publication Detail:
Type:  Journal Article     Date:  2011-09-06
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  39     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-22     Completed Date:  2012-04-09     Revised Date:  2013-10-18    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2264-74     Citation Subset:  IM    
Affiliation:
Department of Drug Metabolism, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. hk@lundbeck.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Chromatography, High Pressure Liquid
Female
Glucuronides / pharmacokinetics*
Humans
Magnetic Resonance Spectroscopy
Male
Mass Spectrometry
Microsomes, Liver / metabolism
Piperazines / pharmacokinetics*
Sulfides / pharmacokinetics*
Chemical
Reg. No./Substance:
0/Glucuronides; 0/Piperazines; 0/Sulfides; 3O2K1S3WQV/vortioxetine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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