METABOLISM OF RACEMIC 3,4-METHYLENEDIOXYETHYLAMPHETAMINE IN HUMANS - ISOLATION, IDENTIFICATION, QUANTIFICATION, AND SYNTHESIS OF URINARY METABOLITES

Studies on the isolation, identification, quantification, and synthesi s of the urinary metabolites of racemic 3,4-methylenedioxyethylampheta mine (MDE) in humans are presented. After oral administration of 140 m g of racemic MDE to healthy volunteers, the following phase I metaboli tes could be isolated and identified by GC/MS: unchanged racemic MDE ( I), racemic 3,4-dihydroxyethylamphetamine (II), racemic 4-hydroxy-3-me thoxyethylamphetamine (IIIa), racemic 3,4-methylenedioxyamphetamine (I V), racemic 3,4-dihydroxyamphetamine (V), racemic 4-hydroxy-3-methoxya mphetamine (Vla), methylenedioxyphenylacetone (VII), 3,4-dihydroxyphen ylacetone (VIII), 4-hydroxy-3-methoxyphenylacetone (IXa), 3,4-methylen edioxyhippuric acid (X), and hydroxymethoxyhippuric acid (XII). The pr obable intermediate metabolite 3,4-dihydroxyhippuric acid (XI) could n ot be detected. Therefore, two overlapping phase I metabolic pathways for racemic MDE in humans could be postulated. The first and predomina nt pathway leads, via ring degradation by O-dealkylation, to the corre sponding 3,4-dihydroxy metabolites, which are subsequently methylated at the hydroxyl group at position 3 of the aromatic ring. The second p athway leads, via side chain degradation by N-dealkylation, to the cor responding primary amines (IV, V, and VI). Oxidative N-deamination for ms the substituted phenylacetones, which are degraded to the correspon ding benzoic acids. This is followed by conjugation with glycine to fo rm substituted hippurates. The structures of all of these metabolites were confirmed by chemical syntheses, which are described in this pape r. All of the metabolites containing hydroxy groups are partly excrete d 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 t he MDE dose was eliminated as I, 31.6% as IIIa, and 2.8% as IV within 32 hr.