Investigation of metabolic profile of pimavanserin in rats by ultrahigh‐performance liquid chromatography 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 revealed that there might be the presence 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 the 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 platform. Methods After a single intragastric administration of pimavanserin at a dose of 50 mg kg−1, 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 ultrahigh‐performance liquid chromatography (UHPLC) coupled with FT‐ICR‐MS. Results A total of 23 metabolites were detected and tentatively identified through comparing their mass spectrometry profiles with those of pimavanserin. These metabolites were found in feces (22), bile (21), rat urine (16) and plasma (15). Results demonstrated that metabolic pathways of pimavanserin in rats included dehydrogenation, demethylation, deethylation, depropylation, debutylation, hydroxylation, dihydroxylation and trihydroxylation. Conclusions A total of 22 phase I metabolites of pimavanserin were detected and tentatively identified. This report presents the first study of screening and identification of the metabolites of pimavanserin. The UHPLC/FT‐ICR‐MS method is a powerful tool for exploring and identifying metabolites in complex biological samples.