Metabolism of 3,4-(Methylenedioxy)-methamphetamine
Creators: name: Lim, Heng-Keang
Publisher: name: University of Utah
Year: 2012
Subjects: Pharmacokinetics
Metabolites

description: (RS)-3,4-(Methylenedioxy)methamphetamine (MDMA) is a ring-substituted amphetamine derivative, hence its common reference in the literature as a 'designer drug.' With respect to its pharmacology, MDMA is more closely related to amphetamine than to the hallucinogen mescaline. The structural similarity of MDMA to the neurotoxin, 3,4-(methylenedioxy)amphetamine (MDA), has led to its being listed as a Schedule I drug by the US Drug Enforcement Agency. MDMA is now an established serotonergic neurotoxin in several animal models such as rats, mice and nonhuman primates. Even though the metabolism of MDMA in the rat had not been determined at the time the research reported here was initiated, several investigators had postulated the involvement of metabolite(s) in MDMA-induced neurotoxicity on the basis of the similarity of its neurotoxicity profile to that of another neurotoxin, p-chloroamphetamine. The objective of this research was to elucidate the metabolism of MDMA. Initially, four metabolic pathways of MDMA have been identified in the rat: N-demethylation, O-dealkylation, deamination, and conjugation (O-methylation, O-glucuronidation, and/or O-sulfation). The specific MDMA metabolites that have been identified are 3-hydroxy-4-methoxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxyamphetamine, 3,4-(methylenedioxy)amphetamine, (4-hydroxy-3-methoxyphenyl)acetone, (3,4-(methylenedioxy)phenyl) acetone, and (3,4-dihydroxyphenyl)acetone. Only MDMA and three of its metabolites (MDA, 4-hydroxy-3-methoxymethamphetamine, and 4-hydroxy-3-methoxyamphetamine) were consistently detected in urine, feces, plasma, liver, and brain. Metabolism of MDMA via O-dealkylation, N-demethylation, and O-methylation was also shown to occur in the rat brain. Further investigation resulted in the identification of 6-hydroxy-MDMA in rat liver, plasma and brain. The 6-hydroxy-MDMA is a particularly significant metabolite in view of its structural similarity to such potent neurotoxins as 6-hydroxydopamine and 6-hydroxy-serotonin. Four metabolic pathways of MDMA in the rat (N-demethylation, O-dealkylation, deamination and conjugation) were also shown to occur in men. All but two ((3,4-dihydroxyphenyl)acetone and 6-OH-MDMA) of the metabolites previously reported in the rat were shown to be present in the urine from a MDMA user. A capillary gas chromatography-positive ion chemical ionization mass spectrometry (GC-CI/MS) assay, linear from 1-500 ng/g wet brain tissue, was successfully developed for MDMA, MDA, 4-hydroxy-3-methoxymethamphetamine (HMM) and 4-hydroxy-3-methoxyamphetamine (HMA) in brain tissues. The sensitivity of the assay was sufficient to permit monitoring MDMA and MDA concentrations in the rat brain for up to 24 hr after a subcutaneous injection of 10 mg/kg MDMA. HMM and HMA could be measured for up to 8 and 10 hr, respectively. Stereoselective disposition of MDMA and MDA was observed in the rat as shown by the distortion of the mean enantiomeric ratio (R/S) of MDMA (1.661) and MDA (0.660) in 24-hr urine after administration of a racemic mixture of the drug.