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[ Appendix 4 sec. 2 ] [ Index ] [ Appendix 4 sec. 4 ]

Appendix 4: Bibliography Metabolism

Cho, A.K., Hiramatsu, M., Distefano, E.W., Chang, A.S and Jenden, D.J. Stereochemical Differences in the Metabolism of 3,4-Methylenedioxymethamphetamine in vivo and in vitro: A Pharmacokinetic Analysis. Drug Metabol. Disposition 18 686-691 (1990).

The optical isomers of MDMA were demethylated to form MDA, with the active (+)-isomer being 3x more extensively degraded. The loss of the methylenedioxy group gave N-methyl-alphamethyldopamine proved to be the major metabolite.

Fitzgerald, R.L., Blanke, R., Narasimhachari, N., Glennon, R. and Rosecrans, J. Identification of 3,4-Methylenedioxyamphetamine (MDA) as a Major Urinary Metabolite of 3,4-Methylenedioxymethamphetamine (MDMA). NIDA Research Monograph, #81 321 (1988).

Rats were administered MDMA chronically and, from both the plasma and the excreta, unchanged MDMA and the demethylation product MDA were detected by GCMS as the trifluoroacetamide derivatives.

Fitzgerald, R.L., Blanke, R.V. and Poklis, A. Stereoselective Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in the Rat. Chirality 2 241-248 (1990).

The optical isomers of MDMA and MDA were assayed in the rat, following the administration of MDMA by two different dosages and by two different routes. The S-isomer of MDMA was found to clear more rapidly, resulting in a preferred presence of its metabolite, the S-isomer of MDA. Blood levels, isomer ratios, and half-lives are given.

Fukuto, J.M., Kumagai, Y. and Cho, A.K. Determination of the Mechanism of Demethylenation of (Methylenedioxy)phenyl Compounds by Cytochrome P450 Using Deuterium Isotope Effects. J. Med. Chem. 34 2871-2876 (1991).

Kinetic studies of the demethylenation of several methylenedioxy compounds (including MDMA) have shown, by isotope effects, to be mediated by different mechanisms.

Helmlin, H. -J., Bracher, K., Salamone, S.J. and Brenneisen, R., Analysis of 3,4-Methylenedioxymethamphetamine (MDMA) and its Metabolites in Human Plasma and Urine by HPLC-DAD, GC-MS and Abuscreen-Online. Abstracts from CAT/SOFT Joint Meeting, October 10-16, 1993, Phoenix, Arizona.

Urine and plasma samples were taken from a number of patients being administered 1.5 mg/Kg MDMA for psychotherapy research purposes. Maximum plasma levels (300 ng/mL) were seen at 140 minutes. The main urinary metabolites were 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, both excreted in conjugated form. The two N-demethylated homologues of these compounds were present as minor metabolites. The cross-reactivity of the Abuscreen immunoassay for both the metabolites (including MDA, another metabolite) and the parent drug were determined.

Hiramatsu, M., DiStefano, E., Chang, A.S. and Cho, A.K. A Pharmacokinetic Analysis of 3,4-Methylenedioxy-methamphetamine Effects on Monoamine Concentrations in Brain Dialysates. Europ. J. Pharmacol. 204 135-140 (1991).

The role of the MDMA metabolite, MDA, in the releasing of dopamine, was studied in brain dialysates. It was noted that the plasma levels of MDA were higher following the administration of (+)-MDMA as compared to (-)-MDMA, to the rat.

Hiramatsu, M., Kumagai, Y., Unger, S.E. and Cho, A.K. Metabolism of Methylenedioxymethamphetamine: Formation of Dihydroxymeth-amphetamine and a Quinone Identified as its Glutathione Adduct. J. Pharmacol. Exptl. Therap. 254 521-527 (1990).

Studies were made of the in vitro metabolism of MDMA by rat liver microsomes, of the optical isomers of MDMA. A P- 450 dependent hydrolysis to N,alpha-dimethyl was observed, which was further converted by superoxide oxidation to a metabolite that formed an adduct with glutathione. It is speculated that this pathway may account for some of the irreversible action on serotoninergic neurons.

Kumagai, Y., Lin, L.Y., Schmitz, D.A. and Cho, A.K. Hydroxyl Radical Mediated Demethylenation of (Methylenedioxy)phenyl Compounds, Chem. Res. Toxicol. 4 330-334 (1991).

The oxidative demethylenation of several methylenedioxy compounds such as MDMA has been studied, with two hydroxyl radical generating systems. The various requirements for this metabolic transformation are defined.

Lim, H.K. and Foltz, R.L. Metabolism of 3,4-Methylenedioxymeth-amphetamine (MDMA) in Rat. FASEB Abstracts Vol. 2 No. 5 page A-1060. Abst: 4440.

The metabolism of MDMA in the rat is studied. Seven metabolites have been identified from urine. These are: 4-hydroxy-3-methoxymethamphetamine; 3,4-methylenedioxyamphetamine; 4-hydroxy-3-methoxyamphetamine; 4-methoxy-3-hydroxymethamphetamine; 3,4-methylenedioxyphenylacetone, 3,4-dihydroxyphenyl acetone and 4-hydroxy-3-methoxyphenylacetone

Lim, H.K. and Foltz, R.L. In Vivo and In Vitro Metabolism of 3,4-Methylenedioxymethamphetamine in the Rat: Identification of Metabolites using an Ion Trap Detecor. Chem. Res. Toxicol. 1 370-378(1988).

Four metabolic pathways for MDMA metabolism in the rat have been identified. These are N-demethylation, O-dealkylation, deamination, and conjugation. A total of eight distinct metabolites have been observed and identified.

Lim, H.K. and Foltz, R.L. Identification of Metabolites of 3,4-Methylenedioxymethamphetamine in Human Urine. Chem. Res. Toxicol. 2 142-143 (1989).

The metabolites observed in the rat following MDMA administration are, to a large degree, identical to those found in man. The metabolic paths observed are N-demethylation, O-dealkylation, deamination, and conjugation. The major metabolite in this one individual (an undocumented MDMA user accident victim) is 3-methoxy-4-hydroxymethamphetamine.

Lim, H.K. and Foltz, R.L. Application of Ion Trap MS/MS Techniques for Identification of Potentially Neurotoxic Metabolites of 3,4-Methylenedioxymeth-amphetamine (MDMA). Paper presented at the CAT Quarterly Meeting, February 3, 1990, San Jose, California.

The GCMS analysis of the rat liver metabolites of MDMA has given evidence of ring hydroxylation. Employing MS/MS techniques and unresolved synthetic mixtures, tentative structural assignments have been presented for the hydroxylation of MDMA at all three available ring positions. Another possible metabolite is ring-hydroxylated MDA. A possible neurotoxic role of such products is suggested by their structural relationship to 6-hydroxydopamine.

Lim, H.K. and Foltz, R.L. In vivo Formation of Aromatic Hydroxylated Metabolites of 3,4-Methylenedioxymeth-amphetamine in the Rat: Identification by Ion Trap Tandem Mass Spectrometric (MS/MS and MS/MS/MS) Techniques. Biological Mass Spectrometry 20 677-686 (1991).

Metabolism studies in the rat have shown that MDMA can be hydroxylated at all three possible aromatic positions. The three corresponding compounds with N-demethylation also are formed. The 6-position is favoured. All metabolites are observed in the liver, only the 6-hydroxyl isomer in the brain, and none can be found in urine.

Lim, H.K., Zeng, S., Chei, D.M. and Foltz, R.L. Comparitive Investigation of Disposition of 3,4-(Methylenedioxy)methamphetamine (MDMA) in the Rat and the Mouse by a Capillary Gas Chromatography-Mass Spectrometry Assay based on Perfluorotributylamine-enhanced Ammonia Positive Ion Chemical Ionization . J. Pharmaceut. Biomed. Anal. 10 657-665 (1992).

An assay is described that allows a quantitative measure of MDMA and three of its primary metabolites, methylenedioxamphetamine, 4-hydroxy-3-methoxymethamphetamine and 4-hydroxy-3-methoxyamphetamine. The latter two metabolites were excreted mainly as the glucuronide and sulfate conjugates. The metabolic patterns of the rat and the mouse are compared.

Lin, L., Kumagai, Y., Cho, A.K. Enzymatic and Chemical Demethylenation of (Methylenedioxy)amphetamine and (Methylenedioxy)methamphetamine by Rat Brain Microsomes. Chem Res. Tox. 5 401-406 (1992)

Metabolism of MDA and MDMA by microsomal preparation from rat brains. The products observed were the corresponding catechol derivatives. The oxidizing agents appear to involve both a cytochrome P-450 component and hydroxyl radical.

Yousif, M.Y., Fitzgerald, R.L., Narasimhachari, N., Rosecrans, J.A., Blanke, R.V. and Glennon, R.A. Identification of Metabolites of 3,4-Methylenedioxymethamphetamine in Rats. Drug and Alcohol Dependence. 26 127-135 (1990).

Two metabolites of MDMA have been established as being present in rat urine, by both HPLC and GCMS; these were MDA and 4-hydroxy-3-methoxy-N-methylamphetamine. From HPLC alone, evidence was found for the positional isomer 3-hydroxy-4-methoxy-N-methyl- amphet-amine, for 4-hydroxy-3-methoxy-amphet amine, and for 3,4-dihydroxy- amphetamine, but these were not confirmed by GCMS. MDA was identified in both plasma and brain extracts.