Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs—Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps

Wink, Carina S. D.; Meyer, Golo M. J.; Meyer, Markus R.; Maurer, Hans H.

doi:10.1016/j.toxlet.2015.08.012

Cited by 12 publications

(8 citation statements)

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“…For in vitro studies of DoA, various human liver preparations have been applied (Peters and Meyer 2011), such as microsomes and cytosol (Wink et al 2015b;Richter et al 2016), S9 fractions (Meyer et al 2014f), primary hepatocytes (Castaneto et al 2015), cell cultures (Richter et al 2016), or heterologously expressed single phase I and II enzymes, for example, in yeast (Peters et al 2009;Zollner et al 2010) or insects cells for enzyme kinetics (Meyer et al 2014b, d, e;Wink et al 2015a). Other in vitro models included microbiological transformation of NPS in wastewater (Mardal and Meyer 2014).…”

Section: Hrms For Elucidation Of the Metabolite Structures And Formatmentioning

confidence: 99%

“…HRMS was applied not only for metabolite identification, but also for quantification of the substrates and/or products in enzyme kinetic studies if very low concentration had to be determined, for example, in cytochrome P450 (CYP) initial activity screenings (Meyer et al 2013c(Meyer et al , 2014dRichter et al 2016;Wink et al 2016), for kinetics of CYPs (Meyer et al 2013aWink et al 2015a), N-acetyl transferases (NAT) (Meyer et al 2014b, e), or esterases (Meyer et al 2014f), or in testing for CYP inhibition by DoA (Dinger et al 2014a, b, 2016a. Cece-Esencan et al…”

Section: Hrms For Studying Pharmacokinetics and Toxicokineticsmentioning

confidence: 99%

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High-resolution mass spectrometry in toxicology: current status and future perspectives

Maurer

Meyer

2016

Arch Toxicol

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This paper reviews high-resolution mass spectrometry (HRMS) approaches using time-of-flight or Orbitrap techniques for research and application in various toxicology fields, particularly in clinical toxicology and forensic toxicology published since 2013 and referenced in PubMed. In the introduction, an overview on applications of HRMS in various toxicology fields is given with reference to current review articles. Papers concerning HRMS in metabolism, screening, and quantification of pharmaceuticals, drugs of abuse, and toxins in human body samples are critically reviewed. Finally, a discussion on advantages as well as limitations and future perspectives of these methods is included.

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Section: Hrms For Elucidation Of the Metabolite Structures And Formatmentioning

confidence: 99%

Section: Hrms For Studying Pharmacokinetics and Toxicokineticsmentioning

confidence: 99%

High-resolution mass spectrometry in toxicology: current status and future perspectives

Maurer

Meyer

2016

Arch Toxicol

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“…Diarylethylamines are in fact, analogues of the now withdrawn and controlled drug lefetamine (12), which was introduced as an opioid analgesic in the 1940s and marketed as Santenol [44].…”

Section: Fig 2 Lefetamine-derived Dissociative Anaestheticsmentioning

confidence: 99%

“…Nonetheless its amphetamine-like stimulant properties had already been described in the 1940s [48]. From the metabolites collected from rat urine, it was inferred that ephenidine was completely metabolised and most likely underwent a combination of N-alkylation, mono-and bishydroxylation of the benzyl ring followed by methylation of one of the two hydroxyl group metabolites at phase 1, and hydroxylation of the phenyl ring after N-dealkylation, glucuronidation and sulfation of all hydroxylated metabolites in phase 2 [48] Since the metabolism of ephenidine has been found to involve at least four CYP-450 enzymes to varying degrees, it has been purported that ephenidine may not give rise to significant drugdrug or drug-food interactions [44].…”

Section: Fig 2 Lefetamine-derived Dissociative Anaestheticsmentioning

confidence: 99%

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An overview of emerging and new psychoactive substances in the United Kingdom

Beharry

Gibbons

2016

Forensic Science International

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The purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug fora and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review the 'user reviews' on drugs fora were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were use alone were considered. Each of the classes contained drugs that are modelled on existing illegal materials and are now covered by the UK New Psychoactive Substances Bill in 2016. AbstractThe purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug fora and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review, the 'user reviewers' on drugs fora were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were used alone were considered.Each of the classes contained drugs that are modelled on existing illegal materials and will be covered by the UK New Psychoactive Substances Bill in 2016.

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Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC‐MS, LC‐MSⁿ, and LC‐HR‐MSⁿ

Wink

Michely

Jacobsen‐Bauer

et al. 2016

Drug Testing and Analysis

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Diphenidine is a new psychoactive substance (NPS) sold as a 'legal high' since 2013. Case reports from Sweden and Japan demonstrate its current use and the necessity of applying analytical procedures in clinical and forensic toxicology. Therefore, the phase I and II metabolites of diphenidine should be identified and based on these results, the detectability using standard urine screening approaches (SUSAs) be elucidated. Urine samples were collected after administration of diphenidine to rats and analyzed using different sample workup procedures with gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-(high resolution)-mass spectrometry (LC-(HR)-MS). With the same approaches incubates of diphenidine with pooled human liver microsomes (pHLM) and cytosol (pHLC) were analyzed. According to the identified metabolites, the following biotransformation steps were proposed in rats: mono- and bis-hydroxylation at different positions, partly followed by dehydrogenation, N,N-bis-dealkylation, and combinations of them followed by glucuronidation and/or methylation of one of the bis-hydroxy-aryl groups. Mono- and bis-hydroxylation followed by dehydrogenation could also be detected in pHLM or pHLC. Cytochrome-P450 (CYP) isozymes CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were all capable of forming the three initial metabolites, namely hydroxy-aryl, hydroxy-piperidine, and bis-hydroxy-piperidine. In incubations with CYP2D6 hydroxy-aryl and hydroxy-piperidine metabolites were detected. After application of a common users' dose, diphenidine metabolites could be detected in rat urine by the authors' GC-MS as well as LC-MS SUSA. Copyright © 2016 John Wiley & Sons, Ltd.

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Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs—Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps

Cited by 12 publications

References 13 publications

High-resolution mass spectrometry in toxicology: current status and future perspectives

High-resolution mass spectrometry in toxicology: current status and future perspectives

An overview of emerging and new psychoactive substances in the United Kingdom

Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC‐MS, LC‐MSⁿ, and LC‐HR‐MSⁿ

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Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs—Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps

Cited by 12 publications

References 13 publications

High-resolution mass spectrometry in toxicology: current status and future perspectives

High-resolution mass spectrometry in toxicology: current status and future perspectives

An overview of emerging and new psychoactive substances in the United Kingdom

Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC‐MS, LC‐MSn, and LC‐HR‐MSn

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Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC‐MS, LC‐MSⁿ, and LC‐HR‐MSⁿ