Structural elucidation of phase I and II metabolites of bupivacaine in horse urine and fungi of the <i>Cunninghamella</i> species using liquid chromatography/multi‐stage mass spectrometry

Rydevik, Axel; Bondesson, Ulf; Hedeland, Mikael

doi:10.1002/rcm.6225

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…A large group of synthetic local analgesics, such as lignocaine, bupivacaine, and procaine, are used therapeutically to block pain and illegally as a local nerve block to mask lameness in horses prior to competition. The development of MS detection methods enabled the analysis by GC‐MS of lignocaine in urine 143 and by LC‐MS of procaine and bupivacaine in plasma 221 and procaine and bupivacaine in urine 222 …”

Section: Resultsmentioning

confidence: 99%

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Doping detection in animals: A review of analytical methodologies published from 1990 to 2019

Moreira

Carmo

Pinho

et al. 2021

Drug Testing and Analysis

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Despite the impressive innate physical abilities of horses, camels, greyhounds, or pigeons, doping agents might be administered to these animals to improve their performance. To control these illegal practices, anti‐doping analytical methodologies have been developed. This review compiles the analytical methods that have been published for the detection of prohibited substances administered to animals involved in sports over 30 years. Relevant papers meeting the search criteria that discussed analytical methods aiming to detect and/or quantify doping substances in animal biological matrices published from 1990 to 2019 were considered. A total of 317 studies were included, of which 298 were related to horses, demonstrating significant advances toward the development of doping detection methods for equine sports. However, analytical methods for the detection of doping agents in sports involving other species are lacking. Due to enhanced accuracy and specificity, chromatographic analysis coupled to mass spectrometry detection is preferred over immunoassays. Regarding biological matrices, blood and urine remain the first choice, although alternative biological matrices, such as hair and feces, have been considered. With the increasing number and type of drugs used as doping agents, the analytes addressed in the published papers are diverse. It is very important to continue to detect and quantify these drugs, recognizing those that are most frequently used, in order to punish the abusers, protect animals' health, and ensure a healthier and genuine competition.

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Section: Resultsmentioning

confidence: 99%

“…The development of MS detection methods enabled the analysis by GC-MS of lignocaine in urine 143 and by LC-MS of procaine and bupivacaine in plasma 221 and procaine and bupivacaine in urine. 222…”

Section: Analgesics And/or Anestheticsmentioning

confidence: 99%

Doping detection in animals: A review of analytical methodologies published from 1990 to 2019

Moreira

Carmo

Pinho

et al. 2021

Drug Testing and Analysis

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“…In vitro metabolic models based on fungi could be useful alternatives to chemical synthesis and in vivo administration, as they are generally cheap, easy to handle, without ethical concerns and as the procedures are easily scalable (Zhang et al 1995;Pearce & Lushnikova 2006). A genus of fungi that has been investigated regarding drug biotransformation is Cunninghamella (Zhang et al 1995;Ma et al 2007;Tevell Åberg et al 2009Tevell Åberg et al , 2010Rydevik et al 2012). However, to the best of the authors' knowledge, the metabolism of arylpropionamide SARMs by Cunninghamella fungi has not been previously studied.…”

Section: Research Articlementioning

confidence: 98%

The fungusCunninghamella eleganscan produce human and equine metabolites of selective androgen receptor modulators (SARMs)

et al. 2012

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1. Selective androgen receptor modulators (SARMs) are a group of substances that have potential to be used as doping agents in sports. Being a relatively new group not available on the open market means that no reference materials are commercially available for the main metabolites. In the presented study, the in vitro metabolism of SARMs by the fungus Cunninghamella elegans has been investigated with the purpose of finding out if it can produce relevant human and equine metabolites. 2. Three different SARMs, S1, S4 and S24, were incubated for 5 days with C. elegans. The samples were analysed both with and without sample pretreatment using ultra performance liquid chromatography coupled to high resolution mass spectrometry. 3. All the important phase I and some phase II metabolites from human and horse were formed by the fungus. They were formed through reactions such as hydroxylation, deacetylation, O-dephenylation, nitro-reduction, acetylation and sulfonation. 4. The study showed that the fungus produced relevant metabolites of the SARMs and thus can be used to mimic mammalian metabolism. Furthermore, it has the potential to be used for future production of reference material.

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“…Furthermore, it is simple to screen several different model strains at the same time and it is easy to scale up the models for the production of large quantities of metabolites that can be used for further investigations. Fungi from the family Cunninghamella are a group of microbial models that have been used to investigate the metabolism of different drugs, for example meloxicam, [18] bupivacaine, [19] trantinterol, [20] doxepine, [21] and selective androgen receptor modulators (SARMs). [22] Moreover, they have been shown to possess different enzymes for phase II metabolism including glutathione S-transferase.…”

Section: Introductionmentioning

confidence: 99%

A novel trapping system for the detection of reactive drug metabolites using the fungus Cunninghamella elegans and high resolution mass spectrometry

Rydevik

Hansson

Hellqvist

et al. 2014

Drug Testing and Analysis

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A new model is presented that can be used to screen for bioactivation of drugs. The evaluation of toxicity is an important step in the development of new drugs. One way to detect possible toxic metabolites is to use trapping agents such as glutathione. Often human liver microsomes are used as a metabolic model in initial studies. However, there is a need for alternatives that are easy to handle, cheap, and can produce large amounts of metabolites. In the presented study, paracetamol, mefenamic acid, and diclofenac, all known to form reactive metabolites in humans, were incubated with the fungus Cunninghamella elegans and the metabolites formed were characterized with ultra high performance liquid chromatography coupled to a quadrupole time of flight mass spectrometer. Interestingly, glutathione conjugates formed by the fungus were observed for all three drugs and their retention times and MS/MS spectra matched those obtained in a comparative experiment with human liver microsomes. These findings clearly demonstrated that the fungus is a suitable trapping model for toxic biotransformation products. Cysteine conjugates of all three test drugs were also observed with high signal intensities in the fungal incubates, giving the model a further indicator of drug bioactivation. To our knowledge, this is the first demonstration of the use of a fungal model for the formation and trapping of reactive drug metabolites. The investigated model is cheap, easy to handle, it does not involve experimental animals and it can be scaled up to produce large amounts of metabolites.

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Structural elucidation of phase I and II metabolites of bupivacaine in horse urine and fungi of the Cunninghamella species using liquid chromatography/multi‐stage mass spectrometry

Cited by 8 publications

References 20 publications

Doping detection in animals: A review of analytical methodologies published from 1990 to 2019

Doping detection in animals: A review of analytical methodologies published from 1990 to 2019

The fungusCunninghamella eleganscan produce human and equine metabolites of selective androgen receptor modulators (SARMs)

A novel trapping system for the detection of reactive drug metabolites using the fungus Cunninghamella elegans and high resolution mass spectrometry

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