Contribution of human esterases to the metabolism of selected drugs of abuse

Meyer, Markus R.; Schütz, Aline; Maurer, Hans H.

doi:10.1016/j.toxlet.2014.10.026

Cited by 32 publications

(29 citation statements)

References 22 publications

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“…The use of both enantiomer specific chromatography [34] and the levels of ethylphenidate detected with "normal" chromatography allow determination of the source of ethylphenidate. The studies [12][13][14] also showed that significant increases (~40% of mean) in the C max concentration of methylphenidate were observed when methylphenidate is combined with ethanol, this adds confirmation that ethanol is an inhibitor of the hCES1 enzyme and as hCES1 is also responsible for the metabolism of ethylphenidate [30] that concomitant ethanol and ethylphenidate use would lead to higher blood concentrations of ethylphenidate. In the course of the studies [12,13] it was also determined that there are "poor" methylphenidate metabolisers in which ~100 times higher concentrations of methylphenidate were observed.…”

Section: Resultsmentioning

confidence: 81%

“…Ethylphenidate, like its analogue methylphenidate has been shown to be initially metabolised to the pharmacologically inactive ritalinic acid (in phase I) by carboxylesterase 1C (hCES1c) [30], one of a group of carboxylesterases that commonly metabolise ester containing drugs (such as heroin and cocaine) [31]. Although full metabolic studies into ethylphenidate have not been carried out to date it is expected that ethylphenidate would follow a similar metabolic profile to methylphenidate [32].…”

Section: Resultsmentioning

confidence: 99%

“…It is likely as the same enzyme metabolises both ethyl and methylphenidate that ethylphenidate would also be affected [30], and that concomitant administration of a drug such as heroin (which is also metabolised by hCES1a [30]) and other potent inhibitors of carboxylesterase such as ethanol, digitonin, telmisartan [36], aripiprazole, fluoxetine [37] and loperamide [38] could also cause increases in the blood levels of ethylphenidate if taken concomitantly, potentially to fatal levels.…”

Section: Resultsmentioning

confidence: 99%

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Seven fatalities associated with ethylphenidate

Maskell

Smith

Cole

et al. 2016

Forensic Science International

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Ethylphenidate is a stimulant novel psychoactive substance that is an analogue of the prescription drug methylphenidate (Ritalin ®. Methylphenidate is used commonly for the treatment of attention deficit hyperactivity disorder. Due to its stimulant effects ethylphenidate is being abused. There is a single case report of a death associated with ethylphenidate in Germany, and a case series of 19 deaths in the East of Scotland, but otherwise, the contribution of ethylphenidate to death is poorly documented. We report the analytical results of 7 cases (between February 2013 and January 2015) in which ethylphenidate was detected and quantitated with a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The individuals (all male) ranged in age from 23 to 49 years (median 25 years). The concentration of ethylphenidate in the cases ranged from 0.026 mg/L to 2.18 mg/L in unpreserved post-mortem femoral blood. Only one case had ethylphenidate present as a sole drug. All other cases had at least 2 other drug classes present (benzodiazepines, heroin, methadone antipsychotics, other new psychoactive compounds). Ethylphenidate toxicity was the sole contribution to the cause of death in one case. Hanging was the cause of death in 2 cases, with the other 4 cases being reported as having occurred due to mixed drug toxicity. These data will further help with the interpretation of post-mortem ethylphenidate levels.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Seven fatalities associated with ethylphenidate

Maskell

Smith

Cole

et al. 2016

Forensic Science International

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“…Metabolic efficacy of human esterases upon drugs of abuse has been studied [23]. In the present work, a titrimetric technique has been successfully employed to investigate and to measure the distribution of esterase activities in different rat brain regions such as spinal cord, telencephalon, mesencephalon, diencephalon, cerebellum and medulla oblongata.…”

Section: Discussionmentioning

confidence: 99%

Titrimetric and parallel voltammetric sensitivity to heroin metabolism in brain

Crespi¹

2017

Brain Nerves

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A titrimetric technique has been successfully employed to measure esterase activities in different tissues. We have applied this tech nique to investigate the distribution of the esterase enzymes in spinal cord and five different brain areas of the rat (telencephalon, mesencephalon, diencephalon, cerebellum and medulla oblongata). The presence of non-specific esterase activity has been determined using alpha-napthyl acetate, a widely employed substrate for these en zymes, whereby the possible existence of "heroin-esterases" has been tested. Our results suggest that the activity of cerebral esterase's on heroin can be studied selectively at pH 8.5, showing quantitative differences in the distribution of these so-called " heroin-es terases" in spinal cord and in the five brain areas studied.In parallel, the efficacy of such "heroin-esterases" has been verified using voltammetric analysis of the influence of the brain enzymes upon the substrate heroin resulting in the evidence of an oxidation signal due to the selective oxidation of uprising morphine.Furthermore, the localization of these enzymes seems to overlap the distribution of brain morphine receptors, suggesting a possible role for these "heroin-esterase" in the metabolism and subsequent ly in the pharmacological activity of heroin, i.e., by converting this drug into morphine.

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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%

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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Contribution of human esterases to the metabolism of selected drugs of abuse

Cited by 32 publications

References 22 publications

Seven fatalities associated with ethylphenidate

Seven fatalities associated with ethylphenidate

Titrimetric and parallel voltammetric sensitivity to heroin metabolism in brain

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

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