High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches

Godinho, Ana L.A.; Martins, Inês L.; Nunes, João; Charneira, Catarina; Grilo, J.; Silva, Diogo; Pereira, Sofia A.; Soto, Karina; Oliveira, M. Conceição; Marques, M. Matilde; Jacob, Cristina C.; Antunes, Alexandra M. M.

doi:10.1016/j.ejps.2018.03.026

Cited by 11 publications

(12 citation statements)

References 33 publications

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“…Samples from the metabolic stability assay were analyzed by LC-MS using the experimental conditions previously described [36]. The in vitro depletion half-life of 7s, t1/2, was calculated using Equation 1, assuming that the compound follows a first-order kinetic trend (see SI Figure S2).…”

Section: Half-life T1/2 Determinationmentioning

confidence: 99%

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Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

et al. 2021

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Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring.

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Section: Half-life T1/2 Determinationmentioning

confidence: 99%

“…The 60 min aliquot was analyzed by LC-HRMS/MS, as previously described [36]. All spectra corresponding to metabolites were then manually checked.…”

Section: Metabolite Identificationmentioning

confidence: 99%

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

et al. 2021

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“…The fragmentation of etravirine is somewhat difficult to understand, because widely different MS–MS spectra have been reported (cf. [ 14 , 58 ]) and accurate- m/z data for etravirine itself were not found; they were only given for the metabolites [ 65 ]. Etravirine ([M+H] + with m/z 435) shows product ions with m/z 144.056 ([C 8 H 5 N 3 ] + ), that is the protonated (4-cyanophenyl)cyanamide, the odd-electron ion with m/z 288.996 ([C 11 H 8 BrN 5 ] +• ) due to the loss of the (4-cyano-2,6-dimethylphenyl)oxidanyl radical (C 9 H 8 NO • ), the ion with m/z 162.950 ([C 3 H 4 BrN 2 O] + ), the ion with m/z 305.998 ([C 11 H 9 BrN 5 O] + ) due to the loss of C 9 H 7 N, and the ion with m/z 303.983 ([C 11 H 7 BrN 5 O] + ) due to the loss of C 9 H 9 N ( Fig.…”

Section: Non-nucleoside Reverse Transcriptase Inhibitors (Nnrtis)mentioning

confidence: 99%

“…2 ). This interpretation is based on metabolism studies [ 65 , 66 ]. The observation of the product ion with m/z 304 for the [D 8 ]-labelled analogue (with labels on the 4-cyano-2,6-dimethylphenyl moiety) [ 67 ] and for the [ 13 C 6 ]-labelled analogues (with labels at the phenyl ring in the 4-cyanophenyl moiety) [ 21 ] also supports part of the interpretation.…”

Section: Non-nucleoside Reverse Transcriptase Inhibitors (Nnrtis)mentioning

confidence: 99%

Tandem mass spectrometry of small-molecule antiviral drugs: 1. HIV-related antivirals

Niessen¹

2020

International Journal of Mass Spectrometry

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Antiviral drugs are a class of compounds developed specifically for the treatment of viral infections. In the development and subsequent application of antiviral drugs, like for any other class of drugs, quantitative analysis in biological matrix is important, e.g., to establish bioavailability, to study pharmacokinetics, and later on possibly for therapeutic drug monitoring. Liquid chromatography–mass spectrometry (LC–MS) with tandem mass spectrometry (MS–MS) operated in selected-reaction monitoring (SRM) mode is the method of choice in quantitative bioanalysis. As information of the fragmentation of antiviral drugs in MS–MS is very much scattered in the scientific literature, it was decided to collect this information and to review it, not only to understand which product ions are actually used in SRM, but also to assist in other studies, e.g., in the identification of drug metabolites or (forced) degradation products. In this first study, attention is paid to antiviral agents used against HIV infection. The review provides fragmentation schemes of ca. 40 antiviral agents as well as several phosphorylated anabolites. The identity of the product ions used in SRM, i.e., elemental composition and exact- m/z , is tabulated, and more detailed fragmentation schemes are provided.

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“…However, lack of information limits researchers’ understanding of the pharmacokinetic behavior of trepibutone. The study of drug metabolism plays a pivotal role in the drug discovery process (Ezzeldin et al, 2017;Godinho et al, 2018;Shankar et al, 2018), which is necessary to explore the metabolic fate thoroughly. The information regarding case reports associated with biotransformation and identification of metabolites will provide researchers with a better understanding about the activity and risks of trepibutone (Huskey et al, 2016; Iegre et al, 2016; Aras et al, 2017; Glaenzel et al, 2018; He and Wan, 2018; Mizuno et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers

Sun¹,

Yang²,

Liu³

et al. 2019

Front. Pharmacol.

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Trepibutone was widely used for cholelithiasis, cholecystitis, biliary tract dyskinesia, cholecystectomy syndrome, and chronic pancreatitis in clinic. However, few investigations on trepibutone have been conducted. In this study, an accurate, sensitive, and selective analytical method was developed and successfully applied to assess the pharmacokinetic behavior of trepibutone in rats. Trepibutone and carbamazepine (internal standard, IS) were quantified using multiple reaction monitoring (MRM) mode with the transitions of m/z 311.09→265.08 and m/z 237.06→194.08, respectively. The linearity, precision, accuracy, extraction recovery, matrix effect, and stability of the established method were all excellent within acceptable range. A total of 30 metabolites were identified in plasma and urine by Q-Exactive high resolution mass spectrometry, and several common metabolic pathways were observed such as dealkylation, oxidation, reduction, glucuronidation, and so on. This research provides more information on trepibutone in pharmacodynamics and toxicology and will assist the usage of trepibutone in clinical.

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High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches

Cited by 11 publications

References 33 publications

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Tandem mass spectrometry of small-molecule antiviral drugs: 1. HIV-related antivirals

Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers

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