Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

Bussy, Ugo; Boisseau, Renaud; Thobie‐Gautier, Christine; Boujtita, Mohammed

doi:10.1016/j.trac.2015.02.017

Cited by 34 publications

(19 citation statements)

References 74 publications

(99 reference statements)

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“…In this study, a method with a simple setup that enables successfully electrochemical oxidation by using a constant (high) potential was introduced. Although the rate of yield of resulting oxidation products using an analytical cell was not as high as described in the literature [ 28 ], the products can be enriched when using a preparative synthesis cell. The limitation of this technique is given by relatively small yields and the resulting weak signals in the mass spectra.…”

Section: Discussionmentioning

confidence: 99%

“…In electrochemistry, bile acids have not yet been frequently studied compounds, because of their inactivity under various conditions and electrode materials [ 27 ]. First attempts already showed the applicability of the oxidation of cholesterol to oxysterols using a boron-doped diamond electrode [ 28 ]. Another study dealt only with a determination of sterols, but did not consider the generation of oxidation products [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Suarez

Rohn

2018

IJMS

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Bile acids are a subgroup of sterols and important products of cholesterol catabolism in mammalian organisms. Modifications (e.g., oxidation and 7-dehydroxylation) are predominantly exerted by the intestinal microbiota. Bile acids can be found in almost all living organisms, and their concentration and metabolism can be used for the assessment of the pathological and nutritional status of an organism. Electrochemical oxidation is a rapid, relatively inexpensive approach to simulate natural metabolic redox processes in vitro. This technique further allows the identification of oxidative degradation pathways of individual substances, as well as the demonstration of binding studies of generated oxidation products with biologically relevant molecules. When coupling an electrochemical and a high-resolution mass spectrometric system, oxidation products can be generated and identified directly by non-targeted ESI-MS. Here, a method for the generation of oxidation products of the primary bile acids cholic acid and chenodeoxycholic acid was exemplarily developed. Most products and the highest intensities were observed at a pH value of 6. For cholic acid, a high potential of 3 V was necessary, while for chenodeoxycholic acid, a potential of 2.4 V led to a higher number of oxidation products. In a second approach, a binding study with glutathione was performed to simulate phase II metabolism. It was possible to detect signals of free glutathione, free bile acids, and adducts of both reactants. As the resulting mass spectra also showed some new signals of the oxidized bile acid, which could not be observed without glutathione, it can be assumed that glutathione is able to bind reactive oxidation species before reacting with other products.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Suarez

Rohn

2018

IJMS

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“…Electrochemistry and MS are a powerful combination for resolving a wide range of (bio)chemical analysis problems. This combined approach has been used to study reaction mechanisms, to detect compounds otherwise not ionized (83), to mimic the oxidative (drug) metabolism normally catalyzed by the cytochrome P450 enzyme family (84,85), or to modify proteins in the field of proteomics (86,87). We have recently reviewed the design aspects of microreactors for coupling to MS (57).…”

Section: Electrochemical Microreactors Combined With Mass Spectrometrymentioning

confidence: 99%

Nanoscale Electrochemical Sensing and Processing in Microreactors

Odijk

Berg

2018

Annual Rev. Anal. Chem.

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In this review, we summarize recent advances in nanoscale electrochemistry, including the use of nanoparticles, carbon nanomaterials, and nanowires. Exciting developments are reported for nanoscale redox cycling devices, which can chemically amplify signal readout. We also discuss promising high-frequency techniques such as nanocapacitive CMOS sensor arrays or heterodyning. In addition, we review electrochemical microreactors for use in (drug) synthesis, biocatalysis, water treatment, or to electrochemically degrade urea for use in a portable artificial kidney. Electrochemical microreactors are also used in combination with mass spectrometry, e.g., to study the mimicry of drug metabolism or to allow electrochemical protein digestion. The review concludes with an outlook on future perspectives in both nanoscale electrochemical sensing and electrochemical microreactors. For sensors, we see a future in wearables and the Internet of Things. In microreactors, a future goal is to monitor the electrochemical conversions more precisely or ultimately in situ by combining other spectroscopic techniques.

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“…Since the major class of reactions in phase I metabolism are oxidation reactions [ 3 ], also non-enzymatic methods could be used for rapid phase I reactions to eliminate drug candidates with an undesired metabolism. Apart from electrochemistry approaches [ 4 , 5 ], titanium dioxide (TiO 2 ) photocatalysis is a simple non-enzymatic method to generate oxidation reaction products similar to those obtained by phase I biochemical transformations [ 6 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

TiO₂ Photocatalyzed Oxidation of Drugs Studied by Laser Ablation Electrospray Ionization Mass Spectrometry

Geenen

Franssen

Miikkulainen

et al. 2019

J. Am. Soc. Mass Spectrom.

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In drug discovery, it is important to identify phase I metabolic modifications as early as possible to screen for inactivation of drugs and/or activation of prodrugs. As the major class of reactions in phase I metabolism is oxidation reactions, oxidation of drugs with TiO 2 photocatalysis can be used as a simple non-biological method to initially eliminate (pro)drug candidates with an undesired phase I oxidation metabolism. Analysis of reaction products is commonly achieved with mass spectrometry coupled to chromatography. However, sample throughput can be substantially increased by eliminating pretreatment steps and exploiting the potential of ambient ionization mass spectrometry (MS). Furthermore, online monitoring of reactions in a time-resolved way would identify sequential modification steps. Here, we introduce a novel (time-resolved) TiO 2 -photocatalysis laser ablation electrospray ionization (LAESI) MS method for the analysis of drug candidates. This method was proven to be compatible with both TiO 2 -coated glass slides as well as solutions containing suspended TiO 2 nanoparticles, and the results were in excellent agreement with studies on biological oxidation of verapamil, buspirone, testosterone, andarine, and ostarine. Finally, a time-resolved LAESI MS setup was developed and initial results for verapamil showed excellent analytical stability for online photocatalyzed oxidation reactions within the set-up up to at least 1 h. Graphical Abstract Electronic supplementary material The online version of this article (10.1007/s13361-018-2120-x) contains supplementary material, which is available to authorized users.

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Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

Cited by 34 publications

References 74 publications

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Nanoscale Electrochemical Sensing and Processing in Microreactors

TiO₂ Photocatalyzed Oxidation of Drugs Studied by Laser Ablation Electrospray Ionization Mass Spectrometry

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Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

Cited by 34 publications

References 74 publications

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Nanoscale Electrochemical Sensing and Processing in Microreactors

TiO2 Photocatalyzed Oxidation of Drugs Studied by Laser Ablation Electrospray Ionization Mass Spectrometry

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TiO₂ Photocatalyzed Oxidation of Drugs Studied by Laser Ablation Electrospray Ionization Mass Spectrometry