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
{"title":"新型前列腺素类药物硝基前列腺素主要生物降解产物的LC-MS/MS鉴定及结构表征。","authors":"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","doi":"10.2174/1872312812666180309160927","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>The aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its major biodegradation products.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"12 1","pages":"54-61"},"PeriodicalIF":0.0000,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound.\",\"authors\":\"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\",\"doi\":\"10.2174/1872312812666180309160927\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>The aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its major biodegradation products.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":11339,\"journal\":{\"name\":\"Drug metabolism letters\",\"volume\":\"12 1\",\"pages\":\"54-61\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2018-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug metabolism letters\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1872312812666180309160927\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug metabolism letters","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1872312812666180309160927","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound.
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.
期刊介绍：
Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
