In vivo and in vitro metabolism of 3,4-(methylenedioxy)methamphetamine in the rat: identification of metabolites using an ion trap detector

Abstract

Four biotransformation pathways of 3,4-(methylenedioxy)methamphetamine (MDMA) in the rat have been identified: 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 (MDA), (4-hydroxy-3-methoxyphenyl)acetone, [3,4-(methylenedioxy)phenyl]acetone, and (3,4-dihydroxyphenyl)acetone. All except 3,4-dihydroxymethamphetamine were present in the urine. The hydroxylated metabolites were excreted in the urine as the O-glucuronide and/or O-sulfate conjugates, but traces of free 4-hydroxy-3-methoxymethamphetamine and 4-hydroxy-3-methoxyamphetamine were also present in unhydrolyzed urine. N-Demethyl and 3-O-methyl phenolic amine metabolites of MDMA were consistently present in brain, liver, blood, and feces. MDMA was metabolized by the 10000g rat liver supernatant to 4-hydroxy-3-methoxymethamphetamine, 3,4-dihydroxymethamphetamine, MDA, and [3,4-(methylenedioxy)phenyl]acetone. Also, the 10000g rat brain supernatant metabolized MDMA to 4-hydroxy-3-methoxymethamphetamine, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxyamphetamine, and MDA.

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

“…Lim and Foltz (1988) identified and determined the distribution of MDMA metabolites in the rat via ion trap mass spectrometry based on their electron ionization and chemical ionization mass spectra. In vitro metabolism was measured by incubating brain and liver samples in an MDMA-containing mixture for 2 h (Lim and Foltz, 1988). The distribution of the metabolites is shown in Table 1 Foltz, 1988, 1991a,b).…”

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

“…1). 8,9) These quinones are highly active redox molecules, which can enter redox cycles with their semiquinone radicals, leading to formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). 10,11) The toxicity of these metabolites has been corre- lated with electron transfer (ET), ROS formation and consequent oxidative stress (OS).…”

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

“…N-Me-␣-MeDA and ␣-MeDA are highly redox-unstable catechols and are conjugated with sulfate and glucuronic acid. Both catechols can also be rapidly oxidized to their corresponding orthoquinones and form adducts with glutathione (GSH) and other thiol-containing compounds (Lim and Foltz, 1988;Hiramatsu et al, 1990). Alternatively, N-Me-␣-MeDA and ␣-MeDA can be O-methylated to form 4-hydroxy-3-methoxymethamphetamine (3-O-Me-N-Me-␣-MeDA) or 4-hydroxy-3-methoxyamphetamine (3-O-Me-␣-MeDA), respectively.…”