title: In vitro and in vivo metabolism and inhibitory activities of vasicine, a potent acetylcholinesterase and butyrylcholinesterase inhibitor.
abstract: Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer's disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Wei
authors: W
authors: Liu
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Xiaoyuan
authors: X
authors: Shi
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Yadi
authors: Y
authors: Yang
authors: Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.
authors: Xuemei
authors: X
authors: Cheng
authors: Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.
authors: Qing
authors: Q
authors: Liu
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Han
authors: H
authors: Han
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Baohua
authors: B
authors: Yang
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Chunyong
authors: C
authors: He
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.
authors: Yongli
authors: Y
authors: Wang
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Bo
authors: B
authors: Jiang
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China; The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.
authors: Zhengtao
authors: Z
authors: Wang
authors: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China; The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China.
authors: Changhong
authors: C
authors: Wang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D008297:Male; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D011799:Quinazolines; C019592:vasicine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase