Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

Abstract

Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples from 16 healthy participants receiving 125 mg of MDMA orally in a controlled study were analyzed using liquid chromatography-tandem mass spectroscopy after chiral derivatization. Pharmacokinetic parameters of R-and S-stereoisomers were determined. Sulfates of 3,4-dihydroxymethamphetamine (DHMA), and sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA) were identified, whereas free phase I metabolites were not detected. Stereoselective differences in C max and AUC 24 were observed with the following preferences: R>S for MDMA and DHMA 4-sulfate; S>R for 3,4-methylenedioxyamphetamine (MDA), DHMA 3-sulfate, and HMMA glucuronide; and no preference in C max for HMMA sulfate. R/S ratios were >1 for all analytes after 24 hours, independent of the initial chiral preference. These are the first data on chiral pharmacokinetics of MDMA phase II metabolites in human plasma in vivo after controlled administration. The main human MDMA metabolites were shown to be sulfate and glucuronide conjugates.

Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans

“…Furthermore, recent studies discussed DHMA to play a role in acute cardiovascular effects observed after MDMA consumption [ 54 ]. It was shown that the initial CYP2D6 metabolite DHMA is not present in human plasma in its free form but rather as its sulfate conjugates [ 23 , 55 ], thus making meaningful interpretations of the impact of CYP2D6 difficult because at least one additional metabolic step occurs. Such an analysis after conjugate cleavage will not represent the actual abundance of all metabolites that are present in plasma, thus complicating correlations with potential neurotoxicity.…”

“…HMMA can be further conjugated by UDP-glucuronyltransferases (UGTs) or SULTs. DHMA 3-sulfate, HMMA sulfate, and HMMA glucuronide were shown to be the main metabolites in plasma [ 23 ] and urine [ 24 ], whereas free DHMA and HMMA were not detectable or only in negligible amounts. A minor pathway includes demethylation to MDA, mainly by CYP2B6, CYP1A2, and CYP3A4 [ 25 , 26 ], followed by demethylenation, O -methylation, and conjugation [ 27 – 29 ].…”

“…A minor pathway includes demethylation to MDA, mainly by CYP2B6, CYP1A2, and CYP3A4 [ 25 , 26 ], followed by demethylenation, O -methylation, and conjugation [ 27 – 29 ]. Differences in the metabolism and plasma pharmacokinetics of the two enantiomers of MDMA were reported in vitro [ 26 , 30 – 32 ] and in vivo [ 9 , 23 , 33 – 36 ], with higher R -MDMA blood concentrations and preferred elimination (metabolism and excretion) of S -stereoisomers.…”

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

“…131,137,138 Additionally, the enantiomers of MDMA are metabolized at different rates, with the R-enantiomer having a longer half-life than the S -enantiomer. 139,140, 141 …”

Interspecies In Vitro Evaluation of Stereoselective Protein Binding for 3,4-Methylenedioxymethamphetamine

“…Even though MDMA is ingested in its racemic form, metabolism of rac-MDMA is stereoselective with (+)-(S)-MDMA being preferentially metabolised [5,6] and more potent in inducing euphoria and energy [7,8], whereas the (−)-(R)-MDMA exert higher hallucinogen-like activity than the (+)-(S)-MDMA [9]. This is evident in the stereoselectivity observed in the concentrations of MDMA and related metabolites in urine and plasma samples [10][11][12][13][14].…”