Metabolism of racemic 3,4-methylenedioxyethylamphetamine in humans. Isolation, identification, quantification, and synthesis of urinary metabolites.

Studies on the isolation, identification, quantification, and synthesis of the urinary metabolites of racemic 3,4-methylenedioxyethylamphetamine (MDE) in humans are presented. After oral administration of 140 mg of racemic MDE to healthy volunteers, the following phase I metabolites could be isolated and identified by GC/MS: unchanged racemic MDE (I), racemic 3,4-dihydroxyethylamphetamine (II), racemic 4-hydroxy-3-methoxyethylamphetamine (IIIa), racemic 3,4-methylenedioxyamphetamine (IV), racemic 3,4-dihydroxyamphetamine (V), racemic 4-hydroxy-3-methoxyamphetamine (VIa), methylenedioxyphenylacetone (IXa), 3,4-methylenedioxyhippuric acid (X), and hydroxymethoxyhippuric acid (XII). The probable intermediate metabolite 3,4-dihydroxyhippuric acid (XI) could not be detected. Therefore, two overlapping phase I metabolic pathways for racemic MDE in humans could be postulated. The first and predominant pathway leads, via ring degradation by O-dealkylation, to the corresponding 3,4-dihydroxy metabolites, which are subsequently methylated at the hydroxyl group at position 3 of the aromatic ring. The second pathway leads, via side chain degradation by N-dealkylation, to the corresponding primary amines (IV, V, and VI). Oxidative N-deamination forms the substituted phenylacetones, which are degraded to the corresponding benzoic acids. This is followed by conjugation with glycine to form substituted hippurates. The structures of all of these metabolites were confirmed by chemical syntheses, which are described in this paper. All of the metabolites containing hydroxy groups are partly excreted in a conjugated form, because the amounts of these metabolites were much higher in urine extracts after enzymatic cleavage of conjugates. Quantification of the urinary excretion by HPLC revealed that 19% of the MDE dose was eliminated as I, 31.6% as IIIa, and 2.8% as IV within 32 hr.