Chiral analysis of carvedilol and its metabolites hydroxyphenyl carvedilol and O-desmethyl carvedilol in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical pharmacokinetic study

Nardotto, Glauco Henrique Balthazar; Coelho, Eduardo Barbosa; Marques, Maria Paula; Lanchote, Vera Lúcia

doi:10.1016/j.jchromb.2016.02.028

Cited by 12 publications

(9 citation statements)

References 16 publications

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“…LC-MS applications mainly concern the clinical and pharmaceutical fields (Bakhtiar et al, 2004 ). Nardotto et al ( 2016 ) used LC/MS/MS systems to investigate patients with type 2 diabetes mellitus treated with an oral dose of racemic carvedilol, who showed accumulation in plasma. Mueller et al applied this technique to measure plasma concentrations of trimethylamine-N-oxide, betaine and choline in the evaluation of patients with suspected coronary artery disease (Mueller et al, 2015 ).…”

Section: Volatile and Non-volatile Compounds: Detection Methods And Dmentioning

confidence: 99%

Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health

2016

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The gut microbiota is composed of a huge number of different bacteria, that produce a large amount of compounds playing a key role in microbe selection and in the construction of a metabolic signaling network. The microbial activities are affected by environmental stimuli leading to the generation of a wide number of compounds, that influence the host metabolome and human health. Indeed, metabolite profiles related to the gut microbiota can offer deep insights on the impact of lifestyle and dietary factors on chronic and acute diseases. Metagenomics, metaproteomics and metabolomics are some of the meta-omics approaches to study the modulation of the gut microbiota. Metabolomic research applied to biofluids allows to: define the metabolic profile; identify and quantify classes and compounds of interest; characterize small molecules produced by intestinal microbes; and define the biochemical pathways of metabolites. Mass spectrometry and nuclear magnetic resonance spectroscopy are the principal technologies applied to metabolomics in terms of coverage, sensitivity and quantification. Moreover, the use of biostatistics and mathematical approaches coupled with metabolomics play a key role in the extraction of biologically meaningful information from wide datasets. Metabolomic studies in gut microbiota-related research have increased, focusing on the generation of novel biomarkers, which could lead to the development of mechanistic hypotheses potentially applicable to the development of nutritional and personalized therapies.

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Section: Volatile and Non-volatile Compounds: Detection Methods And Dmentioning

confidence: 99%

Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health

2016

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“…As samples were reanalysed randomly and blinded based on sufficient residual volume, it was further not achievable to select specifically samples during the elimination phase or at the c max . Additionally, the distinct times of maximum concentration of the analytes (in adults: 1–4 h) would demand for a higher number of reanalysed samples 47,48 . However, the unknown impacts of maturation‐dependent enzyme ontogeny on drug metabolism might lead to distinct times of maximum concentration in children.…”

Section: Resultsmentioning

confidence: 99%

Low‐volume LC–MS/MS method for the pharmacokinetic investigation of carvedilol, enalapril and their metabolites in whole blood and plasma: Application to a paediatric clinical trial

Gangnus

Burckhardt

2020

Drug Testing and Analysis

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Evidence‐based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data. Although a few data sets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites are missing. However, for both drug substances, their active metabolites contribute substantially to drug efficacy. As data can hardly be derived from adults owing to the unknown impacts of enzymatic maturation and ontogeny during childhood, customised assays are important to facilitate paediatric evidence‐based pharmacotherapy. Considering ethical paediatric constraints, a low‐volume liquid chromatography coupled to mass spectrometry (LC–MS/MS) assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O‐desmethyl carvedilol, 4‐ and 5‐hydroxyphenyl carvedilol as well as 3‐ and 8‐hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range—between 0.024/0.049 and 50.000 ng/ml—was achieved with good linearity (r ≥ 0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precision, sensitivity and internal standard normalised matrix effects were further successfully validated with the exception of those for 3‐hydroxy carvedilol, which was therefore assessed semi‐quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood‐to‐plasma ratios were determined for all analytes to form the basis for pharmacokinetic modelling. Finally, incurred sample reanalysis of paediatric samples confirmed the reproducibility of the developed low‐volume LC–MS/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children.

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“…Evaluation of the pharmacokinetic study for ( RS )-9, an analogue of carvedilol and pindolol, with a particular focus on metabolites, is required for the correct interpretation of its pharmacodynamic effect [ 12 ], pharmacokinetic properties [ 14 – 16 , 27 , 28 ], and ultimately develop a suitable formulation that will provide the best bioavailability of the studied compound. These studies were also dictated by the proven pharmacological activity of metabolites of β-adrenolytics, sometimes in excess of the activity of the parent compound [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

A preliminary metabolites identification of a novel compound with β-adrenolytic activity

et al. 2021

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Background The identification of main metabolites and assessment of renal excretion of a novel compound with β-adrenolytic activity (2RS)-1-(1H-indol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol, briefly called (RS)-9 or 2F109, were studied in vivo in rat serum, urine, faeces, liver, intestine, lungs and kidneys, and in vitro in rat liver microsomes. Methods Structures of the metabolites have been developed by comparing the high-resolution product ion mass spectra of metabolites and the parent compound based on the differences in mass values of main fragments. Quantitative analysis of (RS)-9 was done using a system of liquid chromatography coupled with a triple quadrupole mass spectrometer API 2000. Identification studies of predicted metabolites were made by a high-resolution mass spectrometer LTQ XL Orbitrap Discovery and using a Roxy™ system, for online electrochemical mimicry of oxidative metabolism by cytochrome P450s connected to QTRAP 5500. Results For (RS)-9 (m/z 357.2084) phase I metabolites derived from oxidation process: hydroxyl derivatives (m/z 373.2470) and dihydroxyl derivatives (m/z 389.4318), and phase II metabolites: N-methylated compound (m/z 371.1612), O-glucuronide (m/z 533.5118), and sulfate (m/z 437.2350) were identified. Conclusion (RS)-9 was extensively metabolised to several phase I and II metabolites, and renal excretion was a minor route in its elimination. Graphic abstract

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Chiral analysis of carvedilol and its metabolites hydroxyphenyl carvedilol and O-desmethyl carvedilol in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical pharmacokinetic study

Cited by 12 publications

References 16 publications

Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health

Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health

Low‐volume LC–MS/MS method for the pharmacokinetic investigation of carvedilol, enalapril and their metabolites in whole blood and plasma: Application to a paediatric clinical trial

A preliminary metabolites identification of a novel compound with β-adrenolytic activity

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