Investigation of metabolic profile of pimavanserin in rats by UHPLC combined with Fourier transform ion cyclotron resonance mass spectrometry

Rationale Pimavanserin, a selective serotonin 2A receptor inverse agonist, is a promising candidate for treating Parkinson's disease psychosis. Our previous study exhibited that there might be an existence of extensive metabolites of pimavanserin in rats. However, the metabolic fate of pimavanserin in vivo remains unknown. Thus, it is essential to develop an efficient method to investigate metabolic profile of pimavanserin in rats. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to date has the highest mass measurement accuracy and resolution of any mass spectrometry platforms. Methods After a single intragastric administration of pimavanserin at a dose of 50 mg/kg, plasma, bile, urine and feces were collected from rats. A novel and efficient strategy was developed to analyze the metabolic profile of pimavanserin in vivo based on ultra high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (UHPLC/FT-ICR-MS). Results A total of 23 metabolites were detected and tentatively identified through comparing their mass spectrometry profiles with those of pimavanserin. Among these metabolites, feces (22), bile (21), rat urine (16) and plasma (15) were obtained. Results demonstrated that metabolic pathways of pimavanserin in rats included dehydrogenation, demethylation, deethylation, depropylation, debutylation, hydroxylation, dihydroxylation, and trihydroxylation reaction. Conclusions A total of 22 phase I metabolites of pimavanserin were detected and tentatively identified. This study presents the first report of screening and identifying the metabolites of pimavanserin. UHPLC/FT-ICR-MS method was a powerful tool to explore and identify metabolites in complex biological samples.