Title:LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound
VOLUME: 12 ISSUE: 1
Author(s):Natalia V. Mesonzhnik*, Natalia E. Moskaleva, Ksenia M. Shestakova, Ksenya O. Kurynina, Pavel A. Baranov, Natalia M. Gretskaya, Igor V. Serkov, Igor I. Lyubimov, Vladimir V. Bezuglov and Svetlana A. Appolonova
Affiliation:Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997, Institute of Physiologically Active Compounds RAS, Chernogolovka, 142432, LLC , Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997, Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991
Keywords:Multi-target drugs, Nitroproston, prostaglandins, metabolism, asthma, obstructive bronchitis, LC-MS.
Abstract:Background: Nitroproston is a novel prostaglandin-based compound modified by NOdonating
groups with potential application in obstructive respiratory diseases such as asthma and obstructive
bronchitis. Nitroproston has been extensively studied using various pharmacological models.
Its biological stability is still uncertain.
Objective: The aim of the present study was to evaluate Nitroproston stability in vitro, as well as to
identify and characterize its major biodegradation products.
Methods: The principal biodegradation products of Nitroproston were identified in vitro using liquid
chromatography/ion trap – time-of-flight mass-spectrometry. The postulated structure of metabolites
was confirmed using authentic reference standards. Rat, rabbit and human plasma and human whole
blood samples were used for comparative in vitro degradation study. Nitroproston and its biodegradation
products in biological samples were measured by liquid chromatography/triple –stage quadrupole
mass spectrometry.
Results: Nitroproston is rapidly hydrolyzed in rat plasma to generate glycerol-1,3-dinitrate and prostaglandin
E2. The latter can undergo conversion to cyclopentenone prostaglandins A2 and B2. Thereby
less than 5% of the parent compound was observed in rat plasma at the first moment of incubation. A
similar pattern was observed for rabbit plasma where half-life (T1/2) of Nitroproston was about 2.0
minutes. Nitroproston biodegradation rate for human plasma was the slowest (T1/2 = 2.1 h) among
tested species, occurred more rapidly in whole blood (T1/2 = 14.8 min).
Conclusion: It was found that Nitroproston is rapidly hydrolyzed in rodent compared to human plasma
incubations. Whereas Nitroproston is relatively stable in human plasma an enhanced hydrolytic activity
was observed in whole human blood incubations. Extensive metabolism of Nitroproston in human
whole blood was mainly associated with red blood cells. The observed interspecies variability highlights
the need of suitable animal model selection for Nitroproston follow-up PK/PD studies.
