title: Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.
abstract: TPN729 has been reported as a novel phosphodiesterase type 5 (PDE5) inhibitor to treat erectile dysfunction, and is currently being tested in clinical trials. In addition to the potent inhibition against PDE5, TPN729 is regarded as a better alternative to provide fewer side effects and better patient compliance. Given the potential therapeutic benefits of TPN729, it is of great importance to elucidate its metabolic characteristics in drug development. This study is the first to investigate the metabolic fate of TPN729 in humans. A rapid and reliable analytical method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) was established to investigate the metabolic profiles of TPN729 in human plasma, urine, and feces after its oral administration. As a result, a total of 22 metabolites were identified, of which seven were confirmed in comparison with the reference substances. The incubations of the metabolite references in human hepatocytes and aldehyde trapping experiment were further conducted to investigate its metabolic pathways. The results of the present study indicated the extensive metabolism of TPN729 in humans, including oxidative deamination, oxidative ring opening, N-dealkylation, N-oxidation, hydroxylation, dehydrogenation, lactam formation, and glucuronidation. M3 resulting from N-dealkylation was the major circulating substance detected in human plasma. The principal metabolites detected in human feces were products of oxidative deamination and oxidative ring opening. The parent drug was identified as the major component in urine. Taken together, this study provided valuable information on the metabolic fate of TPN729 in humans, and applicable analytical strategies for rapid metabolic elucidation in complex matrix samples through the useful and reliable UPLC/Q-TOF MS technique.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China.
authors.forename: Pan
authors.initials: P
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China. Electronic address: dfzhong@simm.ac.cn.
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
mesh_terms: D000284:Administration, Oral; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D058986:Phosphodiesterase 5 Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D011744:Pyrimidinones / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011744:Pyrimidinones; D013449:Sulfonamides; C000610093:TPN729
keywords: Human; Metabolic pathways; Metabolite identification; Sildenafil; TPN729; UPLC/Q–TOF MS