Studies addressing potential bioactivation and genotoxicity liabilities of the <i>N</i> -nitroso derivative of the antidepressant paroxetine

The mutagenicity and bioactivation potential of <i>N</i>-nitrosoparoxetine, a <i>N</i>-nitrosamine drug substance related impurity (NDSRI) of the marketed antidepressant paroxetine, was characterised <i>in vitro</i>.<i>N</i>-Nitrosoparoxetine was not mutagenic in an OECD 471-compliant bacterial reverse mutation assay even under experimental conditions that supported oxidative metabolism by CYP enzymes. The major biotransformation pathways of <i>N</i>-nitrosoparoxetine paralleled the ones previously noted with paroxetine. Virtually all stable metabolites of <i>N</i>-nitrosoparoxetine in human, rat, and hamster liver tissue were derived from phase 2 conjugations on an unstable catechol intermediate, generated from the oxidative 1,3-benzodioxole ring scission by CYP enzymes. The piperidine ring in <i>N</i>-nitrosoparoxetine was resistant to the α-carbon oxidation step leading to piperidine ring scission, and to the eventual formation of a DNA-reactive electrophilic species.CYP reaction phenotyping studies demonstrated that paroxetine was exclusively metabolised by human CYP2D6, whereas <i>N</i>-nitrosoparoxetine was subject to metabolism by multiple human CYP isoforms including CYP2C19, CYP2D6, and CYP3A4.Whether most NDSRIs derived from parent amine precursors that are resistant to α-carbon oxidation by CYPs will also be devoid of a mutagenic response <i>in vitro</i> needs to be scrutinised further with additional examples to bolster structure-genotoxicity relationships of complex NDSRIs.