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Neurotoxic Metabolites of Ecstasy Accumulate in Rat Brain Following Multiple Injections
Author(s) -
Erives Gladys V,
Lau Serrine S,
Monks Terrence J
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1134-a
Subject(s) - mdma , ecstasy , cmax , chemistry , pharmacology , neurotoxicity , metabolite , toxicokinetics , hallucinogen , pharmacokinetics , toxicity , medicine , biochemistry , psychiatry , organic chemistry
3,4‐(±)‐Methylenedioxymethamphetamine (MDMA, ecstasy) is a serotonergic toxicant. MDMA is demethylenated by cytochrome(s) P450 to the catechol metabolite N‐methyl‐α‐methyldopamine (N‐Me‐α‐MeDA). Thus, the neurotoxicity of MDMA appears to be dependent on peripheral metabolism. We have shown that thioether (glutathione (GSyl) and N‐acetylcysteine (NACSyl) conjugates of N‐Me‐α‐MeDA are neurotoxic and present in the striatum of rats following administration of MDMA. We analyzed concentrations of MDMA metabolites in striatal dialysate. Rats were treated with saline or MDMA (4 x 20mg/kg, s.c.) every 12 h. Concentrations of 5‐GSyl‐N‐Me‐α‐MeDA after each dose were maximum between 30–60 min after drug injection. Although the Cmax values for 5‐GSyl‐N‐Me‐α‐MeDA were similar after each dose (23.0–26.6 pmol/10 μl), the AUC increased 9% after the third. Cmax values for 2,5‐bis‐GSyl‐N‐Me‐α‐MeDA increased from 29.4 to 39.4 pmol/10 μl after each dose and the AUC increased ~50% between the first and fourth injection. Peak concentrations of 5‐NACSyl‐N‐Me‐α‐MeDA and 2,5‐bis‐NACSyl‐N‐Me‐α‐MeDA occurred between 120–180 min after drug injections. The time to reach ½Cmax for 5‐NACSyl‐N‐Me‐α‐MeDA decreased by 45% between the first (124 min) and fourth (68 min) injections, and the AUC for both 5‐NACSyl‐N‐Me‐α‐MeDA and 2,5‐bis‐NACSyl‐N‐Me‐α‐MeDA increased (26% and 46%) respectively. The time to reach ½Cmax for 5‐NACSyl‐N‐Me‐α‐MeDA decreased by 80% between the first (85 min) and fourth (17.5 min) injections, concomitant with increases in the Cmax from 33.0 pmol/10 μl to 49.5 pmol/ 10 μl, possibly because processes for its elimination became saturated. The data indicate that thioether metabolites are achievable after repeated dosing suggesting that these metabolites of MDMA may accumulate in brain following multiple dosing. (P30 ES 06694)