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Forced Degradation Study of an Anti-Diabetic Drug Imeglimin: Impurity Profiling and Structure Elucidation Using lc-q-tof-ms/ms and NMR

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RAPID COMMUNICATIONS IN MASS SPECTROMETRY 2025年第5期39卷 e9960页

作者： Gogikar, Shiva Kumar Sen, Sibu Pathinti, Shivashankar Samanthula, Gananadhamu Dikundwar, Amol G. Natl Inst Pharmaceut Educ & Res NIPER Dept Pharmaceut Anal Hyderabad India

RationaleThe present study aims to establish structures of the degradation products of an anti-diabetic drug, Imeglimin (IMG) approved for the treatment of type 2 diabetes mellitus in the year 2021. Degradation pathways are proposed along with in silico toxicity assessments of the observed degradation products (DPs) of the *** reversed-phase high-performance liquid chromatography (RP-HPlc), equipped with a photodiode array detector, was used to separate the observed DPs with a Phenomenex Luna PFP (250 x 4.6 mm, 5 mu m) column, using 10 mM ammonium formate (pH 4.5) and methanol as mobile phase. Liquid chromatography quadrupole time of flight mass spectrometry (lc-q-tof-ms/ms) and nuclear magnetic resonance (NMR) spectroscopy were employed for structural elucidation. Zeneth and Derek suites were used for in silico *** total of four degradation products were observed, which were successfully separated on an RP-HPlc. The structural characterization of three of the four DPs was achieved using lc-q-tof-ms/ms by employing electro spray ionization as well as atmospheric pressure chemical ionization. Additionally, DP-3 was isolated using a preparative HPlc and was characterized by NMR. Computationally predicted structures were compared with the experimental *** HPlc method, capable of separating the Imeglimin and its four DPs, was developed and validated as per the ICH q2(R1) guideline. Structure elucidation reveals a variety of products with metformin as one of the identified DPs along with a metabolite. The toxicity potential of DPs was assessed through docking studies.

关键词： forced degradation Imeglimin lc-q-tof-ms/ms metformin toxicity

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In vivo and in vitro metabolite profiling of nirmatrelvir using lc-q-tof-ms/ms along with the in silico approaches for prediction of metabolites and their toxicity

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BIOMEDICAL CHROMATOGRAPHY 2024年第5期38卷 e5849-e5849页

作者： Chaganti, Sowmya Kushwah, Bhoopendra Singh Velip, Laximan Tiwari, Shristy S. Chilvery, Shrilekha Godugu, Chandraiah Samanthula, Gananadhamu Natl Inst Pharmaceut Educ & Res Dept Pharmaceut Anal Hyderabad Telangana India Natl Inst Pharmaceut Educ & Res Dept Pharmacol Hyderabad Telangana India Natl Inst Pharmaceut Educ & Res Dept Pharmaceut Anal Balanagar Hyderabad 500037 Telangana India

Nirmatrelvir (NRV), a 3C-like protease or M-pro inhibitor of SARS-CoV-2, is used for the treatment of COVID-19 in adult and paediatric patients. The present study was accomplished to investigate the comprehensive metabolic fate of NRV using in vitro and in vivo models. The in vitro models used for the study were microsomes (human liver microsomes, rat liver microsomes, mouse liver microsomes) and S9 fractions (human liver S9 fractions and rat liver S9 fractions) with the appropriate cofactors, whereas Sprague-Dawley rats were used as the in vivo models. Nirmatrelvir was administered orally to Sprague-Dawley rats, which was followed by the collection of urine, faeces and blood at pre-determined time intervals. Protein precipitation was used as the sample preparation method for all the samples. The samples were then analysed by liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (lc-q-tof-ms/ms) using an Acquity BEH C18 column with 0.1% formic acid and acetonitrile as the mobile phase. Four metabolites were found to be novel, which were formed via amide hydrolysis, oxidation and hydroxylation. Furthermore, an in silico analysis was performed using Meteor Nexus software to predict the probable metabolic changes of NRV. The toxicity and mutagenicity of NRV and its metabolites were also determined using DEREK Nexus and SARAH Nexus.

关键词： characterization DEREK lc-q-tof-ms/ms Meteor nirmatrelvir SARAH

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Metabolic analysis of the illegal analogues of anti-obesity drugs using lc-q-tof-ms/ms

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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 2021年 1163卷 122502-122502页

作者： Jeong, Daseul Choe, Sanggil Lee, Sooyeun Kim, Kang Min Pyo, Jaesung Kyungsung Univ Coll Pharm Busan 48434 South Korea Seoul Inst Natl Forens Serv Forens Toxicol Sect 139 Jiyangro Seoul 08036 South Korea Keimyung Univ Coll Pharm 1095 Dalgubeoldaero Daegu 42601 South Korea Kyungsung Univ Dept Pharmaceut Sci & Technol Busan 48434 South Korea

With an increase in the obese population, the indiscriminate demand for anti-obesity drugs for rapid weight loss or maintenance has grown. As a result, illegal substances that could induce unexpected negative health effects or fatal side effects are being produced and mixed into consumer products. In the present study, the metabolites of five major illegal anti-obesity drugs are analyzed for the first time. Our data can be utilized to identify related compounds and predict their toxicological effects. Didesmethylsibutramine, desmethylsibutramine, homosibutramine, chlorosibutramine, and benzylsibutramine were metabolized in in vitro and in vivo models, and the metabolites were identified using liquid chromatography quadrupole-time of flight mass spectrometry (lc-qtof-ms) and tandem mass spectrometry (lc-q-tof-ms/ms). The in vivo metabolite analysis was carried out using urine and feces samples from rats, and the in vitro metabolite analysis was performed by incubating the analogues with human liver microsomes. We found that each sibutramine analogue was metabolized into several constituents: 2 (M1-2), 5 (M1-5), 11 (M1-11), 7 (N1-7), and 5 (O1-5). In conclusion, our metabolic study could be used for toxicological detection of illegal obesity treatments and metabolite identification in forensic cases.

关键词： Sibutramine Analogues Metabolites lc-q-tof-ms/ms

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Determination of anti-hyperglycaemic activity in steroidal glycoside rich fraction of lily bulbs and characterization of the chemical profiles by lc-q-tof-ms/ms

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Journal of Functional Foods 2014年 6卷 585-597页

作者： Mengdi Zhu Jianguang Luo Huawei Lv Lingyi Kong State Key Laboratory of Natural Medicines Department of Natural Medicinal Chemistry China Pharmaceutical University 24 Tong Jia Xiang Nanjing 210009 People’s Republic of China

The bulbs of Lilium brownii Brown var. viridulum Baker (lily) are commonly known as “Bai-he” for both functional food and medicine in China. In this study, the combination of bio-assay guided fractionation and chemical analysis revealed that steroidal glycoside rich L. brownii fraction (SGL) exhibited potential anti-hyperglycaemic activity. Further investigations demonstrated that SGL could increase glucose consumption in HepG2 cells and 3T3-L1 adipocytes by 1.61- and 2.13-fold, respectively, and enhance 3T3-L1 preadipocyte differentiation. Total 29 steroidal glycosides in SGL were positively or tentatively identified using liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (lc-q-tof-ms/ms), which afforded us a comprehensive understanding of the bioactive fraction. These results suggested that steroidal glycosides in L. brownii possessed desirable potential in glucose metabolism and insulin sensitivity. This is the first report on the determination of anti-hyperglycaemic activity in steroidal glycoside rich fraction of lily bulbs and characterization of the chemical profiles by lc-q-tof-ms/ms.

关键词： Lily bulbs Anti-hyperglycaemic activity Steroidal glycosides lc-q-tof-ms/ms

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Sorption and desorption of per-fluoroalkyl substances (PFAS) on waste containment liner components

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JOURNAL OF ENVIRONMENTAL MANAGEMENT 2025年 381卷 125288页

作者： Mikhael, Elissar Bouazza, Abdelmalek Gates, Will P. Monash Univ Dept Civil Engn 23 Coll Walk Melbourne Vic 3800 Australia Deakin Univ Inst Frontier Mat Melbourne Burwood Campus221 Burwood Highway Melbourne Vic 3125 Australia

This paper examines the sorption kinetics, isotherms and desorption behaviour of six per-fluoroalkyl substances (PFAS) from single-and multi-compound solutions with various landfill liner materials currently in use and those proposed for future lining systems. The compounds examined include perfluorooctanesulfonic acid, perfluorooctanoic acid, perfluorohexanoic acid, perfluorobutanesulfonic acid, pentafluoropropionic acid and trifluoromethanesulfonic acid. The impact of landfill leachate on the sorption properties of selected liner components, namely geotextiles, bentonite and a proposed bentonite modifier, was also investigated. No significant competitive effects on sorption were observed at typical environmental PFAS concentrations (1-80 nM). Biexponential and pseudo-second-order kinetics models sufficiently described the sorption process. Furthermore, the Freundlich isotherm model generally provided a better fit to the experimental data than the Langmuir model. The maximum PFAS sorption capacity for each material followed the order: ion exchange resin > activated carbon amended bentonite > clays > nonwoven polypropylene geotextile > woven polypropylene geotextile > bentonite > polyester nonwoven geotextile. Sorption generally increased with longer carbon-chain lengths, with sulfonate species exhibiting a stronger affinity than carboxylic acids. The desorption of PFAS from the liner constituents aligned with their sorption behaviour. The presence of matrix co-constituents in leachate reduced the sorptive affinity of most PFAS. The results suggest that incorporating activated carbon into geosynthetic clay liners may reduce the migration of long-chain PFAS but may be less effective for shorter-chain compounds. Adding additional sorptive materials to lining systems, such as ion exchange resins, may be necessary to effectively attenuate short and ultrashort PFAS compounds.

关键词： CMC critical micelle concentration DI deionised DOC dissolved organic carbon GAC granular activated carbon GCL geosynthetic clay liner HPlc high performance liquid chromatography lc-ms/ms liquid chromatography tandem mass spectrometry lc-q-tof-ms/ms liquid chromatography-quadrupole time-of-flight tandem mass spectrometry instrument LOq limit of quantification MDL method detection limit NOM natural organic matter PFASs per- and poly-fluoroalkyl substances PFBS perfluorobutane sulfonate PFCAs perfluorocarboxylic acids PFHxA perfluorohexanoic acid PFHxS perfluorohexanesulfonic acid PFO pseudo first-order PFOA perfluorooctanoic acid PFOS perfluorooctanesulfonic acid PFPrA pentafluoropropionic acid PFSAs perfluorosulfonic acids pKa acid dissociation constant POPs persistent organic pollutants PSO pseudo second order SS suspended solids TFms trifluoromethanesulfonic acid

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A systematic metabolic pathway identification of Common Gardenia Fruit (Gardeniae Fructus) in mouse bile, plasma, urine and feces by HPlc-q-tof-ms/ms

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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 2020年 1145卷 122100-122100页

作者： Zhou, Jing Zhang, Yongjie Li, Ning Zhao, Di Lu, Yang Wang, Lirui Chen, Xijing China Pharmaceut Univ Sch Basic Med & Clin Pharm 639 Longmian Ave Nanjing 211198 Peoples R China Nanjing Univ Chinese Med Affiliated Hosp Integrated Tradit Chinese & Weste Dept Pharmaceut Anal 100 Hongshan Rd Nanjing 210023 Peoples R China China Acad Chinese Med Sci Jiangsu Prov Acad Tradit Chinese Med Dept Metabol 100 Hongshan Rd Nanjing 210028 Peoples R China China Acad Chinese Med Sci Jiangsu Branch 100 Hongshan Rd Nanjing 210028 Peoples R China

Gardeniae Fructus was a traditional Chinese medicine (TCM) containing various biological ingredients including iridoids and crocetins, monocyclic monoterpenes, organic acids, and flavonoids. However, few systematic identification studies of the bioactive components in vivo have been reported. Herein, the ingredients and metabolites of Gardeniae Fructus were investigated using high-performance liquid chromatography coupled with high-sensitivity q-tof mass spectrometry. A total of 45 prototype compounds in Gardeniae Fructus extract were tentatively identified. After oral administration, 69 of prototypes and metabolites were identified from mice bile, plasma, urine, and feces, in which, 31 compounds were prototypes, and 38 chemicals were metabolites. The in vivo biotransformation pathways of these metabolites were also proposed including phase I (hydrolysis, hydrogenation, oxidation, loss of O, and ketone formation, decarboxylation) and phase II reactions (glycine, cysteine, glutathione, and glutamine, and sulfate conjugation, and glucuronidation). For the first time, our results had revealed systematic metabolic profiles of ingredients in Gardeniae Fructus extract in vivo of mice and replenished novel knowledge into the explanation of effective material and/or toxicological basis of Gardeniae Fructus which deserves further investigation.

关键词： Gardeniae Fructus In vivo metabolites traditional Chinese medicine lc-q-tof-ms/ms

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Phenolic profiles and antioxidant activity of Morus alba L. infusions prepared from commercially available products and naturally collected leaves

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SCIENTIFIC REPORTS 2025年第1期15卷 1-12页

作者： Janiak, Michal Adam Gryn-Rynko, Anna Sulewska, Katarzyna Amarowicz, Ryszard Penkacik, Kamila Graczyk, Radomir Olszewska-Slonina, Dorota Majewski, Michal Stanislaw Polish Acad Sci Inst Anim Reprod & Food Res Sci Grp Chem & Phys Properties Food Trylinskiego 18 Str PL-10683 Olsztyn Poland Univ Warmia & Mazury Fac Med Dept Pharmacol & Toxicol Warszawska 30 Str PL-10082 Olsztyn Poland Bydgoszcz Univ Sci & Technol Fac Anim Breeding & Biol Dept Biol & Anim Environm Mazowiecka 28 Str PL-85084 Bydgoszcz Poland Nicolaus Copernicus Univ Torun Fac Pharm Ludw Rydygier Coll Med Bydgoszcz Dept Pathobiochem & Clin Chem M Curie Sklodowskiej 9 Str PL-85094 Bydgoszcz Poland

The aim of this study was to compare the phenolic compound content and antioxidant activity of infusions made from commercially available Morus alba L. leaves with those of infusions made from a naturally collected source. The phenolic profile was determined using RP-HPlc-DAD and lc-q-tof-ms/ms. The total phenolic content (TPC) was determined using Folin-Cioc & acirc;lteu reagent. To assess the antioxidant and reducing properties, Trolox equivalent antioxidant capacity (TEAC) and ferric reducing antioxidant power (FRAP) were used. Our analysis revealed the presence of two phenolic acids and six flavonoids. The most abundant compound was chlorogenic acid. The TPC, TEAC, and FRAP results indicated that infusions prepared from naturally collected samples exhibited greater phenolic content (19.7-52.6 vs 18.1-35.2 mg/100 ml) and stronger antioxidant (0.0605-0.1842 vs 0.0453-0.0822 mmol Trolox/100 ml) and reducing (0.244-0.597 vs 0.202-0.371 mmol Fe2+/100 ml) activities than those of commercially available products in the Polish market. Samples L1-L3 from the natural collection were those with the highest values. These results were further supported by principal component analysis (PCA), which categorized observations into three distinct clusters.

关键词： Morus alba L. Phenolic compounds Antioxidant activity RP-HPlc-DAD Chlorogenic acid lc-q-tof-ms/ms

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Metabolic study of vardenafil analogues: Pseudovardenafil and hydroxyvardenafil

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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 2020年第0期1139卷 121940-000页

作者： Heo, Dayoung Kang, Jae Seon Choe, Sanggil Lee, Sooyeun Kim, Kang Min Pyo, Jaesung Kyungsung Univ Coll Pharm Busan 48434 South Korea Natl Forens Serv Dept Drug & Toxicol Wonju 26460 South Korea Keimyung Univ Coll Pharm 1095 Dalgubeoldaero Daegu 42601 South Korea Kyungsung Univ Dept Pharmaceut Sci & Technol Busan 48434 South Korea

Vardenafil, a remedy for erectile dysfunction, is easily modified, facilitating the creation of analogues that have been illegally added to functional foods and counterfeit medications. However, the medical profile of these analogues, including their safety, efficacy, safe drug combinations, metabolism and excretion, has not been completely evaluated, which could cause serious health problems. In this study, two representative vardenafil analogues, pseudovardenafil and hydroxyvardenafil, were metabolized with in-vitro model (human liver microsome) and in-vivo model (rats). The metabolized samples were extracted and characterized, using liquid chromatography quadrupole-time of flight mass spectrometry (lc-q-tof-ms). Some imprecise interpretations were evaluated with tandem mass spectrometry (lc-q-tof-ms/ms) for mass fragmentation analysis. A total of 11 metabolites of pseudovardenafil and 13 metabolites of hydroxyvardenafil that were identified have never been reported. These new metabolites could be usefully applied to forensic science and other metabolic fields. Furthermore, they could serve as principal references for the toxicity, danger, and side effects of unlawful vardenafil counterfeits.

关键词： Vardenafil analogues Pseudovardenafil Hydroxyvardenafil Metabolites lc-q-tof-ms/ms

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Extraction, characterization and bioactive properties of Nigella sativa seedcake

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JOURNAL OF FOOD SCIENCE AND TECHNOLOGY-MYSORE 2017年第12期54卷 3936-3947页

作者： Kadam, Deepak Lele, S. S. Inst Chem Technol Dept Food Engn & Technol Bombay 400019 Maharashtra India

The extraction of phenolic compounds from Nigella sativa seed cake was optimized in terms of % of EtOH, extraction time, extraction temperature and solid to solvent ratio to maximize the phenolic content yield. The optimized conditions were 40% ethanol for 60 min, at 40 A degrees C, 1/14 solid to sample ratio. The lc-ms profiling of the extract was found to contain many important phenolics such as Kaempferol, p-coumaroyl acid derivative, Thymol-O-sophoroside etc. The extract showed significant antioxidant activity with IC50 values 548.5 +/- 9.4, 64.3 +/- 2.7 mu g/ml and 1.85 +/- 0.2 mM TE/g in terms of DPPH scavenging activity, TEAC, and FRAP assay respectively. The results also indicated that the extract has a significant anti-inflammatory potential. This was evaluated as a measure of the membrane stabilization ability and protein denaturation inhibition capacity (IC50 values) and the activities were found to be 318.73 +/- 6.98 and 150.39 +/- 2.61 mu g/ml respectively. Moreover, results of the study are promising and invite to further investigate the above activities in order to confirm them in different experimental situations and to consider for possible use in a nutraceutical approach.

关键词： Nigella sativa seed cake Box-Behnken experimental design lc-q-tof-ms/ms Antioxidant capacity Phenolic compound

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Human intestine and liver microsomal metabolic differences between C19-diester and monoester diterpenoid alkaloids from the roots of Aconitum carmichaelii Debx.

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TOXICOLOGY IN VITRO 2017年第Part3期45卷 318-333页

作者： Zhang, Min Peng, Chong-sheng Li, Xiao-bo Shanghai Jiao Tong Univ Sch Pharm 800 Dongchuan Rd Shanghai 200240 Peoples R China

The roots of Aconitum carmichaelii Debx. show excellent effects against rheumatism and cardiovascular diseases, but the effective compounds, C-19-diester and monoester diterpenoid alkaloids (DDA5 and MDAs) are toxic for their narrow therapeutic windows. It is noteworthy to investigate intestinal metabolism of these toxic compounds mainly by oral administration, because gut also express drug-metabolizing enzymes as well as liver. This study initially focused on phase I and phase II metabolism of DDAs (including aconitine, mesaconitine and hypaconitine) and MDAs (including benzoylaconine, benzoylmesaconine and benzoylhypaconine) in human intestine microsomes (HIM), with comparison of metabolism in human liver microsomes (HLM). CYP3A in HIM mainly catalyzed phase I metabolism of DDAs and MDAs, with polarity increased. The intestinal metabolic profiles of DDAs were more various than MDAs. No glucuronide metabolites were detected, which was in agreement with HLM metabolism. The results showed that gut played an important role in detoxification of DDAs and MDAs by oral administration. Moreover, eight new metabolites from DDAs were identified in microsomes incubations by UPlc-q-tof-HRms/ms. Our findings provided reference to the detoxification of DDAs and MDAs in the intestine in vivo and supplemented the phase I metabolic pathways for DDAs.

关键词： Diester diterpenoid alkaloids Monoester diterpenoid alkaloids Human intestine microsomes Cytochrome P450 enzymes Uridine 5'-diphosphate-glucuronosyltransferases lc-q-tof-ms/ms

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