Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Mueller, Melanie; Yuan, Jie; Felim, Anne; Neudörffer, Anne; Peters, Frank T.; Maurer, Hans H.; McCann, Una D.; Largeron, Martine; Ricaurte, George A.

doi:10.1124/dmd.109.028340

Cited by 52 publications

(62 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies showed that HHMA and HMMA are formed in vivo after MDMA administration in both rats and humans (Lim et al, 1992;Segura et al, 2001;Valtier et al, 2007;Goni-Allo et al, 2008;Kolbrich et al, 2008b;Mueller et al, 2009), but there is uncertainty about whether these hydroxylated metabolites represent major MDMA metabolites in rodents. Here we observed that AUCs for HHMA and HMMA were always greater than AUC for MDMA in rats given 2.5 mg/kg, confirming that O-demethylenation is the predominant pathway for biotransformation in rats given clinically relevant MDMA doses.…”

Section: Discussionmentioning

confidence: 99%

“…However, few studies have examined MDMA pharmacokinetics in rats given doses of ,10 mg/kg, comparable to those taken by humans (Chu et al, 1996;Starr et al, 2008;, and just one assessed the relationship between pharmacodynamics and pharmacokinetics (Chu et al, 1996). Most MDMA pharmacokinetic studies in rats investigated doses of 10 mg/kg or higher (Valtier et al, 2007;Meyer et al, 2008;Upreti and Eddington, 2008;Mueller et al, 2009). In two rat studies employing doses of ,10 mg/kg, evidence for MDMA nonlinear accumulation was reported (Chu et al, 1996;), similar to the human situation (Mas et al, 1999;de la Torre et al, 2000;Kolbrich et al, 2008b).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

et al. 2013

View full text Add to dashboard Cite

3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (6)-3,4-dihydroxymethamphetamine (HHMA), (6)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (6)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA C max was 164 6 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5-and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3-and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Neurotoxic effects to serotonic neurons have been described, but are still controversial discussed in terms of species and dosing [7][8][9]. MDMA metabolism is suspected to be responsible for neurotoxicity presumably through the formation of glutathion adducts [10][11][12][13][14][15][16]. HMMA can be further conjugated by UDP-glucuronyltransferases or by sulfotransferases.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an LC‐MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy‐methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma

Steuer

Schmidhauser

Liechti

et al. 2014

Drug Testing and Analysis

View full text Add to dashboard Cite

This is the peer reviewed version of the following article: Steuer, A. E., Schmidhauser, C., Liechti, M. E., and Kraemer, T. (2015), Development and validation of an LC-MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy-methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma. Drug Test. Analysis, 7, 592-602, which has been published in final form at http://dx.doi.org/10.1002/dta.1740. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. resulting in the formation of diastereomers which were easily separable on standard reverse phase stationary phases. This simple and fast method was validated according to international guidelines including specificity, recovery, matrix effects, accuracy and precision, stabilities, and limits of quantification. The method proved to be selective, sensitive, accurate and precise for all tested analytes except for DHMA. The method was applied to the analysis of more than 400 samples from a controlled study after application of MDMA.

show abstract

“…Metabolism of MDMA may play a role in this neurotoxicity (Miller et al, 1997;Bai et al, 1999;Mueller et al, 2009). As shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Investigation on the Enantioselectivity of the Sulfation of the Methylenedioxymethamphetamine Metabolites 3,4-Dihydroxymethamphetamine and 4-Hydroxy-3-Methoxymethamphetamine using the Substrate-Depletion Approach

Schwaninger

Meyer²,

Maurer³

2011

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:Different pharmacokinetic properties are known for the two enantiomers of the entactogen 3,4-methylendioxy-methamphetamine (MDMA), most likely due to enantioselective metabolism. The aim of the present work was 1) the investigation of the main sulfotransferases (SULT) isoenzymes involved in the sulfation of the main MDMA phase I metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) and 2) the evaluation of a possible enantioselectivity of this phase II metabolic step. Therefore, racemic DHMA and HMMA were incubated with heterologously expressed SULTs, and quantification of the sulfates by liquid chromatography-high-resolution mass spectrometry was conducted. Because separation of DHMA and HMMA sulfate could not be achieved by liquid chromatography, enantioselective kinetic parameters were determined using the substratedepletion approach with enantioselective quantification of substrate consumption by gas chromatography-negative ion chemical ionization mass spectrometry. SULT1A1 and SULT1A3 catalyzed sulfation of DHMA, and SULT1A3 and SULT1E1 catalyzed sulfation of HMMA. SULT1A1 and SULT1E1 revealed classic Michaelis-Menten kinetics, whereas SULT1A3 kinetics showed deviation from the typical Michaelis-Menten kinetics, resulting in a concentrationdependent self-inhibition. SULT1A3 showed the highest affinity and capacity of the SULT isoforms. Marked enantioselectivity could be observed for S-DHMA sulfation by SULT1A3 and in human liver cytosol, whereas no differences were observed for HMMA sulfation. Finally, comparison of K m and V max values calculated using achiral product formation and chiral substrate depletion showed good correlation within 2-fold of each other. In conclusion, preferences for S-enantiomers were observed for DHMA sulfation, but not for HMMA sulfation. IntroductionThe chiral compound R, R,propane-2-amine], also known as ecstasy, is known as a very popular drug of abuse, but it is also associated with damage of serotonergic neurons (Kalant, 2001;Monks et al., 2004;Easton and Marsden, 2006). Metabolism of MDMA may play a role in this neurotoxicity (Miller et al., 1997;Bai et al., 1999;Mueller et al., 2009). As shown in Fig. 1, one major pathway of MDMA includes cytochrome P450 (P450)-catalyzed O-demethylation to 3,4-dihydroxymethamphetamine (DHMA), followed by O-methylation by catechol-O-methyltransferase (COMT) mainly to 4-hydroxy-3-methoxymethamphetamine (HMMA) and conjugation of DHMA and HMMA by sulfotransferases (SULTs) (Maurer, 1996;Maurer et al., 2000;. In urine samples of recreational MDMA users, more than 90% of DHMA and HMMA are excreted as conjugates, with sulfates present in higher concentrations (Shima et al., 2008; A. E. Schwaninger, M. R. Meyer, A. J. Barnes, E. A. Kolbrich-Spargo, D. A. Gorelick, R. S. Goodwin, M. A. Huestis, and H. H. Maurer, manuscript in preparation). For the two enantiomers of MDMA, differences in their dose-response curves and in their in vivo kinetics were observed (Fallon et al., 1999;Kalant, 2001;Kraemer a...

show abstract

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Abstract: ABSTRACT:The mechanism by which the recreational drug (؎) -

Cited by 52 publications

References 36 publications

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

Development and validation of an LC‐MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy‐methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma

Investigation on the Enantioselectivity of the Sulfation of the Methylenedioxymethamphetamine Metabolites 3,4-Dihydroxymethamphetamine and 4-Hydroxy-3-Methoxymethamphetamine using the Substrate-Depletion Approach

Contact Info

Product

Resources

About