Characterization of fluvoxamine degradation products in postmortem blood by liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry

Fluvoxamine (FLV) is a selective serotonin reuptake inhibitor primarily used to treat obsessive-compulsive disorder. In Japan, FLV is linked to lethal intoxication and suicide cases. Therefore, it is important to establish its exact concentration in postmortem (PM) blood. It has been reported that blood FLV concentration decreases over time. In this study, we aimed to clarify the mechanisms underlying changes in FLV concentration in human blood over time. We examined whether FLV underwent hydroxylation and/or oxidation in a Fenton reaction mixture containing FeCl2, hemoglobin (Hb), or hydrogen peroxide (H2O2) after incubating at 37 °C for 24 h. In addition, we measured FLV and its degradation products in human blood by liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry. Mass spectrometric result indicated the formation of (E)-N-(2-(((5-methoxy-1-(4(trifluoromethyl)phenyl)pentylidene)amino)oxy)ethyl)formamide (FLV-CHO), (E)-5-hydroxy-1-(4-(trifluoromethyl)phenyl)pentan-1-one-O-(2-aminoethyl)oxime (FLD), and (E)-5-(hydroxymethoxy)-1-(4-(trifluoromethyl)phenyl)pentan-1-one-O-(2-aminoethyl)-oxime (FLV-OH) in the reaction mixture. In addition, FLV-CHO concentration in human blood was strongly correlated with percentage FLV degradation relative to its initial concentration. Our results indicate that FLV-CHO, formed by Hb/H2O2-mediated FLV degradation in blood, is a potential biomarker for correcting FLV concentration in PM blood.