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.