Studies on the in vivo contribution of human cytochrome P450s to the hepatic metabolism of glaucine, a new drug of abuse

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

doi:10.1016/j.bcp.2013.08.025

Cited by 16 publications

(15 citation statements)

References 32 publications

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“…22,23 The incubations were performed for 10 minutes except for alpha-PBP, which was incubated for 5 minutes with CYP2C9, alpha-PVT for 2 minutes with CYP2B6, alpha-PHP for 5 minutes with CYP1A2, and alpha-POP The reactions were stopped with 50 μL ice-cold acetonitrile containing 5 μM alpha-PVP as an internal standard. 22,23 The incubations were performed for 10 minutes except for alpha-PBP, which was incubated for 5 minutes with CYP2C9, alpha-PVT for 2 minutes with CYP2B6, alpha-PHP for 5 minutes with CYP1A2, and alpha-POP The reactions were stopped with 50 μL ice-cold acetonitrile containing 5 μM alpha-PVP as an internal standard.…”

Section: Kinetic Studiesmentioning

confidence: 99%

“…Kinetic studies were based on previous publications. 22,23 The incubations were performed for 10 minutes except for alpha-PBP, which was incubated for 5 minutes with CYP2C9, alpha-PVT for 2 minutes with CYP2B6, alpha-PHP for 5 minutes with CYP1A2, and alpha-POP for 5 minutes with CYP1A2. Protein concentrations were between 10 and 30 pmol/mL.…”

Section: Kinetic Studiesmentioning

confidence: 99%

“…Determination of relative amounts was a suitable approach for the calculation of the relative net hepatic clearances. 22 Curve fitting and calculation of enzyme kinetic constants was performed by a nonlinear regression model using GNU R (https://www.r-project.org). The Michaelis-…”

Section: Kinetic Studiesmentioning

confidence: 99%

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Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Manier

Richter

Schäper³

et al. 2018

Drug Testing and Analysis

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In vitro and in vivo experiments are widely used for studying the metabolism of new psychoactive substances (NPS). The availability of such data is required for toxicological risk assessments and development of urine screening approaches. This study investigated the in vitro metabolism of the 5 pyrrolidinophenone-derived NPS alpha-pyrrolidinobutyrophenone (alpha-PBP), alpha-pyrrolidinopentiothiophenone (alpha-PVT), alpha-pyrrolidinohexanophenone (alpha-PHP), alpha-pyrrolidinoenanthophenone (alpha-PEP, PV8), and alpha-pyrrolidinooctanophenone (alpha-POP, PV9). First, they were incubated with pooled human liver microsomes (pHLM) or pooled human liver S9 fraction (pS9) for identification of the main phase I and II metabolites. All substances formed hydroxy metabolites and lactams. Longer alkyl chains resulted in keto group and carboxylic acid formation. Comparing these results with published data obtained using pHLM, primary human hepatocytes (PHH), and authentic human urine samples, PHH provided the most extensive metabolism. Second, enzyme kinetic studies showed that the initial metabolic steps were formed by cytochrome P450 isoforms (CYP) CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 resulting in pyrrolidine, thiophene or alkyl hydroxy metabolites depending on the length of the alkyl chain. The kinetic parameters indicated an increasing affinity of the CYP enzymes with increase of the length of the alkyl chain. These parameters were then used to calculate the contribution of a single CYP enzyme to the in vivo hepatic clearance. CYP2C19 and CYP2D6 were mainly involved in the case of alpha-PBP and CYP1A2, CYP2C9 and CYP2C19 in the case of alpha-PVT, alpha-PHP, alpha-PEP, and alpha-POP.

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Section: Kinetic Studiesmentioning

confidence: 99%

Section: Kinetic Studiesmentioning

confidence: 99%

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Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Manier

Richter

Schäper³

et al. 2018

Drug Testing and Analysis

Self Cite

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“…ODemethyl glaucine was synthesized according to Meyer et al [39]. Ammonium formate (analytical grade) and formic acid (LCeMS grade) were obtained from Fluka (Neu-Ulm, Germany), acetonitrile, methanol (all LCeMS grade) from Fisher Scientific (Schwerte, Germany), water (LCeMS grade) and all other chemicals (analytical grade) from VWR.…”

Section: Reagents and Materialsmentioning

confidence: 99%

Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening – Exemplified for cardiovascular drugs

Helfer

Michely

Weber

et al. 2015

Analytica Chimica Acta

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123

118

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“…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%

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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Studies on the in vivo contribution of human cytochrome P450s to the hepatic metabolism of glaucine, a new drug of abuse

Cited by 16 publications

References 32 publications

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening – Exemplified for cardiovascular drugs

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

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