Received for publication July 17, 2007.
Revised September 26, 2007.
Accepted for publication September 27, 2007.

Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

Abstract

The serotonergic neurotoxicity of 3,4-(±)methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism, since direct injection of into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl--methyldopamine (N-Me--MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me--MeDA are neurotoxic, and are present in rat brain following subcutaneous injection of MDMA. Since multi-dose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg, s. c.) at 12 h intervals for a total of four injections led to a significant accumulation of the N-Me--MeDA thioether metabolites in striatal dialysate. The AUC_0-300min for 5-(glutathion-S-yl)-N-Me--MeDA increased ~ 33% between the first and fourth injection and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me--MeDA. Similarly, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC_0-300min for both 5-(N-acetylcystein-S-yl)-N-Me--MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me--MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me--MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me--MeDA increased by 53% and 28% respectively between the first and third doses. Finally, although the C_max values for the mono-thioether conjugates were essentially unchanged following each injection, the values increased by 38% and ~50%, for 2,5-bis-(glutathion-S-yl)-N-Me--MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me--MeDA respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain following multiple dosing.

Key words: 3,4-(±)-methylenedioxymethamphetamine, glutathione, metabolism, neurotoxicity, pharmacokinetics, transport

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