LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound

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, Svetlana A. Appolonova.

Journal Name: Drug Metabolism Letters

Volume 12 , Issue 1 , 2018

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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.

Keywords: Multi-target drugs, Nitroproston, prostaglandins, metabolism, asthma, obstructive bronchitis, LC-MS.

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Article Details

VOLUME: 12
ISSUE: 1
Year: 2018
Page: [54 - 61]
Pages: 8
DOI: 10.2174/1872312812666180309160927
Price: $58

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