CHARACTERIZATION OF THE METABOLITES OF THE ANTIDEPRESSANT DRUG NEFAZODONE IN HUMAN URINE AND PLASMA

Metabolism of the antidepressant drug nefazodone was studied in humans after single and multiple 50 and 200 mg oral doses of [C-14] nefazodone as part of a single and multiple dose balance study. Deuterium was included in the molecule to facilitate structural characterization of the metabolites by mass spectrometry. Metabolites were isolated from a 0-24 hr pooled urine from three subjects and purified to homogeneity by HPLC. Chemical structures of the metabolites were proposed based on collisionally induced dissociation (CID) and electron impact ionization MS. The profile of radioactivity showed three main urinary metabolites, one of which was a conjugate, and several minor metabolites. The three major metabolites were identified as the phenoxyethyl triazolone propionic acid resulting from N-dealkylation of both nefazodone and hydroxynefazodone (OH-Nef), as well as a corresponding phenoxyethyl triazolone propanel metabolite of N-dealkylated nefazodone, present exclusively as a conjugate. The more polar minor components were not identified. The excretion of total radioactivity in the 24-hr sample was 49% of the dose, of which the identified metabolites comprised 38% of the dose. There was no difference in the qualitative or quantitative urinary profile of the metabolites at 50 or 200 mg dose levels after single or multiple oral dosing. These N-dealkylated metabolites were also present in pooled human plasma samples along with nefazodone, OH-Nef, and an unknown metabolite that was present in plasma in large amounts relative to nefazodone and OH-Nef. This metabolite was isolated from plasma and from a human liver S9 incubation and identified by CID tandem MS and NMR as the triazoledione of nefazodone. A scheme for the metabolism of nefazodone is proposed.