by Nicholas Saunders
[ 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.