Concentrations and Ratios of Amphetamine, Methamphetamine, MDA, MDMA, and MDEA Enantiomers Determined in Plasma Samples from Clinical Toxicology and Driving Under the Influence of Drugs Cases by GC-NICI-MS*

Peters, Frank T.; Samyn, Nele; Wahl, Martin A.; Kræmer, Thomas; Boeck, Gert De; Maurer, Hans H.

doi:10.1093/jat/27.8.552

Cited by 65 publications

(74 citation statements)

References 25 publications

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“…The present data suggest that, over time, tolerance to the pharmacologic effects of MDMA takes place and, as such, preclinical studies may not provide the most appropriate model of MDMA use in a recreational setting, in which experienced users may gradually increase their dose of drug. Our results on plasma concentrations of MDMA in 'ecstasy' consumers who had attended a dance party are in line with those contained in reports on individuals who presented to emergency rooms or came to the attention of authorities after ingesting ecstasy (Samyn et al, 2002;Peters et al, 2003;Lora-Tamayo et al, 2004).…”

Section: Discussionsupporting

confidence: 89%

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

Irvine

Keane

Felgate

et al. 2005

Neuropsychopharmacol

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The increasing use of (7) 3,4-methylenedioxymethamphetamine (MDMA) in the setting of large dance parties ('raves') and clubs has been the source of some concern, because of potential acute adverse events, and because animal studies suggest that MDMA has the potential to damage brain serotonin (5-HT) neurons. However, it is not yet known whether MDMA, as used in the setting of dance parties, leads to plasma levels of MDMA that are associated with toxicity to 5-HT neurons in animals. The present study sought to address this question. Plasma MDMA concentrations, vital signs, and a variety of blood and urine measures were obtained prior to, and hours after, individuals attended a dance party. After the dance party, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of 'ecstasy' and, in some subjects, overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Additional subjects were likely to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications, and suggest that some of these individuals may be at risk for developing MDMA-induced toxicity to brain serotonin neurons.

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Section: Discussionsupporting

confidence: 89%

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

Irvine

Keane

Felgate

et al. 2005

Neuropsychopharmacol

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“…Accordingly, the plasma concentrations of the S-enantiomers of the main metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine and 3,4-methylenedioxyamphetamine (MDA) were much higher than those of the R-enantiomers. Enantioselective pharmacokinetics of MDEA resulting in higher plasma concentrations of R-MDEA were also confirmed by other authors (Spitzer et al, 2001;Meyer et al, 2002;Peters et al, 2003). Enantioselective metabolism is the most likely explanation for the enantioselective pharmacokinetics of MDEA.…”

Section: Introductionsupporting

confidence: 73%

“…CYP2D6 and CYP3A4 should be most important in this context, because together they account for approximately 80% of net clearance especially at low substrate concentrations. This result must be considered when trying to estimate the time of ingestion from dmd.aspetjournals.org enantiomer ratios in plasma as proposed for, e.g., MDMA by Fallon et al (1999) and Peters et al (2003), because the time course of such ratios may be considerably different in CYP2D6 poor metabolizers or in case of inhibition of CYP2D6/CYP3A4 by coingested drugs. In addition, it must be considered that correlation of the presented in vitro data with the in vivo situation is not straightforward, because in vivo DHEA is further metabolized by O-methylation and/or glucuronidation/sulfation.…”

Section: Resultsmentioning

confidence: 99%

The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxyethylamphetamine and Its Single Enantiomers

Meyer¹,

Peters²,

Maurer³

2009

Drug Metab Dispos

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ABSTRACT:The 3,4-methylenedioxy-methamphetamine (MDMA)-related designer drug 3,4-methylenedioxyethylamphetamine (MDEA, Eve) is a chiral compound that is mainly metabolized by N-deethylation and demethylenation during phase I metabolism. The involvement of several cytochrome P450 (P450) isozymes in these metabolic steps has been demonstrated by inhibition assays using human liver microsomes. However, a comprehensive study on the involvement of all relevant human P450s has not been published yet. In addition, the chirality of this drug was not considered in these in vitro studies. The aim of the present work was first to elucidate the contribution of the relevant human P450 isozymes in the demethylenation as well as in the N-dealkylation of racemic MDEA and its single enantiomers and secondly to compare these findings with recently published data concerning the enantioselective metabolism of MDMA. Racemic MDEA and its single enantiomers were incubated using heterologously expressed human P450s, and the corresponding metabolites dihydroxyethylamphetamine and methylenedioxyamphetamine were determined by gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. The highest contributions to both metabolic steps as calculated from the enzyme kinetic data were obtained for CYP3A4 and CYP2D6 at substrate concentrations corresponding to plasma concentrations of recreational users after intake of racemic MDEA. Both metabolic reactions were found to be enantioselective with a general preference for the S-enantiomers, which was particularly pronounced in the case of CYP2C19. In conclusion, different pharmacokinetic properties of MDEA enantiomers observed in vivo are therefore partially caused by P450-dependent enantioselective metabolism. More recently, we have published studies concerning the involvement of human cytochrome P450 (P450) in the metabolism of racemic MDMA as well as the metabolites of its enantiomers (Meyer et al., 2008). In this MDMA study, we were able to show that CYP2C19 (in addition to CYP2D6) is the most enantioselective P450 isozyme enzyme toward the two main metabolic steps, namely N-demethylation and demethylenation, with a preference for the S-enantiomer. These results could in part explain the different pharmacokinetics of R-and S-MDMA in vivo. As shown in Fig. 1, in vivo and in vitro studies showed that the main metabolic steps of MDEA are the same as those of MDMA, namely N-deethylation and demethylenation (Maurer et al., 2000). Later, MDEA was investigated concerning enantioselective pharmacokinetics in vivo (Brunnenberg and Kovar, 2001;Buechler et al., 2003), and the plasma half-life of R-MDEA was found to be longer than that of S-MDEA. Accordingly, the plasma concentrations of the S-enantiomers of the main metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine and 3,4-methylenedioxyamphetamine (MDA) were much higher than those of the R-enantiomers. Enantioselective pharmacokinetics of MDEA resulting in higher plasma concentrations of R-MDEA were also...

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“…Published reports (Peters et al, 2003;Lora-Tamayo et al, 2004; also see Samyn et al, 2002) indicate that some recreational 'ecstasy' consumers who come to the attention of authorities have plasma concentrations of MDMA that overlap those seen here, in monkeys that subsequently develop lasting deficits in brain 5-HT neuronal markers. Findings in asymptomatic 'ecstasy' consumers of (Irvine et al, unpublished observations) are in general agreement with those in symptomatic individuals who presented to emergency rooms, or for some reason (eg driving impairment) came to the attention of authorities in the wake of 'ecstasy'/MDMA use.…”

Section: Comparison To Plasma Mdma Concentrations In 'Ecstasy' Consumersmentioning

confidence: 54%

Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons

Mechan

Yuan

Hatzidimitriou

et al. 2005

Neuropsychopharmacol

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A large body of data indicates that (7)3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can damage brain serotonin neurons in animals. However, the relevance of these preclinical data to humans is uncertain, because doses and routes of administration used in animals have generally differed from those used by humans. Here, we examined the pharmacokinetic profile of MDMA in squirrel monkeys after different routes of administration, and explored the relationship between acute plasma MDMA concentrations after repeated oral dosing and subsequent brain serotonin deficits. Oral MDMA administration engendered a plasma profile of MDMA in squirrel monkeys resembling that seen in humans, although the half-life of MDMA in monkeys is shorter (3 vs 6-9 h). MDMA was biotransformed into MDA, and the plasma ratio of MDA to MDMA was 3-5/100, similar to that in humans. MDMA accumulation in squirrel monkeys was nonlinear, and plasma levels were highly correlated with regional brain serotonin deficits observed 2 weeks later. The present results indicate that plasma concentrations of MDMA shown here to produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational 'ecstasy' consumers, and are two to three times higher than those found in humans administered a single 100-150 mg dose of MDMA in a controlled setting. Additional studies are needed on the relative sensitivity of brain serotonin neurons to MDMA toxicity in humans and non-human primates, the pharmacokinetic parameter(s) of MDMA most closely linked to the neurotoxic process, and metabolites other than MDA that may play a role.

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Concentrations and Ratios of Amphetamine, Methamphetamine, MDA, MDMA, and MDEA Enantiomers Determined in Plasma Samples from Clinical Toxicology and Driving Under the Influence of Drugs Cases by GC-NICI-MS*

Cited by 65 publications

References 25 publications

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

Plasma Drug Concentrations and Physiological Measures in ‘Dance Party’ Participants

The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxyethylamphetamine and Its Single Enantiomers

Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons

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