title: Biosynthesis and identification of an N-oxide/N-glucuronide metabolite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004.
abstract: 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: Department of Drug Metabolism, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. hk@lundbeck.com
authors: Henriette Kold
authors: HK
authors: Uldam
authors: Martin
authors: M
authors: Juhl
authors: Henrik
authors: H
authors: Pedersen
authors: Lars
authors: L
authors: Dalgaard
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics*; D013440:Sulfides / Q000493:pharmacokinetics*; D000078784:Vortioxetine
chemical_list: D020719:Glucuronides; D010879:Piperazines; D013440:Sulfides; D000078784:Vortioxetine