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2-(2 H -Benzotriazol-2-yl)-4,6-di- tert -pentylphenol (UV 328, CAS: 25973-55-1) is an ultraviolet light (UV) absorber which is used as an additive for plastics and other polymeric substances to prevent the host material from light induced degradation reactions. However, no information about human exposure, metabolism and kinetics is available for this substance so far. Therefore, in vitro experiments with human liver microsomes were performed to derive oxidative phase I metabolites of UV 328 in an explorative approach using liquid-chromatography coupled with tandem mass spectrometry. Initially, a suspect screening mode was applied to the incubated samples. Six metabolites with hydroxy or oxo groups as well as a metabolite carrying both hydroxy and carbonyl moieties at the alkyl side chains were postulated and custom synthesized as reference standards. Afterwards, the results were verified in a target screening approach. Thereby, five of the six investigated analyte structures were confirmed. Quantitative estimations of the generated transformation products revealed 2-(2 H -benzotriazol-2-yl)-6-(3-hydroxy-2-methylbutan-2-yl)-4-(tert -pentyl)phenol (UV 328-6/3-OH), 2-(2 H -benzotriazol-2-yl)-4-(3-hydroxy-2-methylbutan-2-yl)-6-(tert -pentyl)phenol (UV 328-4/3-OH) and 2-(2 H -benzotriazol-2-yl)-4-(2-methylbutan-3-on-2-yl)-6-(3-hydroxy-2-methylbutan-2-yl)phenol (UV 328-4/3-CO-6/3-OH) as most promising parameters. In summary, oxidation of both alkyl side chains at the phenol moiety was proven, but no metabolic transformations at the benzotriazole moiety were observed. • Oxidative UV 328 metabolism in human liver microsome assay • Exploration of the metabolism by the conjunction of suspect screening and targeted analyses • Identification and verification of the oxidation at tert-pentyl side chains • Metabolites with hydroxylated tert-pentyl groups occurred as promising parameter of human biomonitoring. [ABSTRACT FROM AUTHOR]

• Pharmacokinetic properties of three pairs of enantiomers were analyzed. • High performance affinity chromatography led to human serum albumin binding of 76–98 % with low enantioselectivity. • Upon incubation with mouse liver microsomes (R)-configured eutomers showed higher metabolic stability than their les potent (S)-enantiomers. • Glucuronidation of the benzylic alcohol showed high enantioselectivity. Recently, the eutomers of highly potent GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold were identified. Herein, pharmacokinetic properties regarding lipophilicity, plasma protein binding (PPB) and metabolism are analyzed. The log D 7.4 values of 1.68 for phenol 1 and 2.46 for methyl ether 2 are in a very good range for CNS agents. A very similar log D 7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (log D 7.4 = 1.49). The herein developed high performance affinity chromatography (HPAC) method using human serum albumin as stationary phase led to PPB of 3-benzazepines (R)- 1 - 3 and (S)- 1 - 3 of 76–98%. Upon incubation with mouse liver microsomes, (R)- 1 - 3 and (S)- 1 - 3 showed moderate to high metabolic stability. The (R)-configured eutomers turned out to be metabolically more stable than their (S)-configured distomers. During phase I metabolism of 3-benzazepines 1 - 3 hydroxylations at both aromatic rings, the aliphatic side chain and the seven-membered ring were observed. O -demethylation of methyl ether (S)- 2 was faster than O -demethylation of its enantiomer (R)- 2. In phase I biotransformation the phenol eutomer (R)- 1 showed comparable stability as ifenprodil. In phase II biotransformation, glucuronidation of the phenolic (only 1) and benzylic hydroxy groups was observed. Both enantiomers formed the same type of metabolites, respectively, but in different amounts. Whereas, the benzylic hydroxy group of (R)- 2 was glucuronidated preferably, predominant benzylic glucuronidation of (S)- 3 was detected. Mouse liver microsomes produced the glucuronide of phenol 1 (main metabolite) in larger amounts than rat liver microsomes. [ABSTRACT FROM AUTHOR]

The central CB 2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB 2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [ 18 F] 7a was reported, which shows high CB 2 affinity and high selectivity over the CB 1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a ( K i  = 7.9 nM) and the ketone 26a ( K i  = 8.6 nM) displayed high CB 2 affinity and CB 2 :CB 1 selectivity in in vitro radioligand binding studies. Incubation of 7a , 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a , but a remarkably higher stability of ketone 26a in comparison to amide 7a . Furthermore, a logD 7.4 value of 5.56 ± 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification. [ABSTRACT FROM AUTHOR]

Recently, the development of the fluorinated PET tracer [ 18 F] 1a for imaging of CB 2 receptors in the central nervous system was reported. [ 18 F] 1a showed high CB 2 affinity and selectivity over the CB 1 subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N -dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents ( 23a , 24a ), modified hydrogenation state ( 26a ) and enlarged fluoroalkyl substituent ( 13a , 13b ) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a , 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b . Partial hydrogenation of the aromatic carbazole system ( 26a ) was not tolerated by the CB 2 receptor. A methylsulfonyl moiety in 6-position ( 24a ) led to considerably reduced CB 2 affinity, whereas a 6-methoxy moiety ( 23a ) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of 1a resulted in fluoroisopropyl derivatives 13 with unchanged high CB 2 affinity and CB 2 : CB 1 selectivity. Compared with the fluoroethyl derivative 1a , the carbazole N -atom of the fluoroisopropyl derivative 13a ( K i (CB 2 ) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N -oxides was not observed and N -dealkylation took place to a less amount. [ABSTRACT FROM AUTHOR]

Introduction: Experiments in metabolomics rely on the identification and quantification of metabolites in complex biological mixtures. This remains one of the major challenges in NMR/mass spectrometry analysis of metabolic profiles. These features are mandatory to make metabolomics asserting a general approach to test a priori formulated hypotheses on the basis of exhaustive metabolome characterization rather than an exploratory tool dealing with unknown metabolic features. Objectives: In this article we propose a method, named ASICS, based on a strong statistical theory that handles automatically the metabolites identification and quantification in proton NMR spectra. Methods: A statistical linear model is built to explain a complex spectrum using a library containing pure metabolite spectra. This model can handle local or global chemical shift variations due to experimental conditions using a warping function. A statistical lasso-type estimator identifies and quantifies the metabolites in the complex spectrum. This estimator shows good statistical properties and handles peak overlapping issues. Results: The performances of the method were investigated on known mixtures (such as synthetic urine) and on plasma datasets from duck and human. Results show noteworthy performances, outperforming current existing methods. Conclusion: ASICS is a completely automated procedure to identify and quantify metabolites in H NMR spectra of biological mixtures. It will enable empowering NMR-based metabolomics by quickly and accurately helping experts to obtain metabolic profiles. [ABSTRACT FROM AUTHOR]

This review focuses on recent and potential advances in chemometric methods in relation to data processing in metabolomics, especially for data generated from mass spectrometric techniques. Metabolomics is gradually being regarded a valuable and promising biotechnology rather than an ambitious advancement. Herein, we outline significant developments in metabolomics, especially in the combination with modern chemical analysis techniques, and dedicated statistical, and chemometric data analytical strategies. Advanced skills in the preprocessing of raw data, identification of metabolites, variable selection, and modeling are illustrated. We believe that insights from these developments will help narrow the gap between the original dataset and current biological knowledge. We also discuss the limitations and perspectives of extracting information from high-throughput datasets. [ABSTRACT FROM AUTHOR]

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UPLC-QTOF-MS/MS was used to identify metabolites in rat blood, urine and feces after the administration of n-butanol extract derived from steamed notoginseng. The metabolic process of saponins came from steamed notoginseng was analyzed. The metabolites were processed by PeakView software, and identified according to the structural characteristics of prototype compounds and the accurate qualitative and quantitative changes of common metabolic pathways. Four saponins metabolites were identified based on MS/MS information of metabolites, namely ginsenoside Rh₄, Rk₃, Rk₁, Rg₅,and their 15 metabolites were verified. The metabolic pathways of the four ginsenosides in n-butanol extract included glucuronidation, desugar, sulfation, dehydromethylation, and branch loss. The metabolites of main active saponin components derived from steamed Panax notoginseng were analyzed from the perspective of qualitative analysis. And the material basis for the efficacy of steamed notoginseng was further clarified., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)