New insights in the metabolism of oxybutynin: evidence of N-oxidation of propargylamine moiety and rearrangement to enaminoketone

Abstract1. Oxybutyninhydrochloride is an antimuscarinic agent prescribed to patients with an overactive bladder(OAB) and symptoms of urinary urge incontinence. Oxybutyninundergoes pre-systemic metabolism, and the N-desethyloxybutynin (Oxy-DE), is reported to have similar anticholinergiceffects.2. We revisited the oxidative metabolic fate of oxybutyninby liquid chromatography– tandem mass spectrometryanalysis of incubations with rat and human liverfractions, and by measuring plasma and urine samples collected after oral administrationof oxybutyninin rats. This investigation highlighted that not only N-deethylation but also N-oxidation participates in the clearance of oxybutyninafter oral administration.3. A new metabolic scheme for oxybutyninwas delineated, identifying three distinct oxidative metabolic pathways: N-deethylation (Oxy-DE) followed by the oxidation of the secondary amine function to form the hydroxylamine(Oxy-HA), N-oxidation (Oxy-NO) followed by rearrangement of the tertiary propa...