Erives Gladys V, Lau Serrine S, Monks Terrence J
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, 1703 E. Mabel Street, Tucson, AZ 85721-0207, USA.
J Pharmacol Exp Ther. 2008 Jan;324(1):284-91. doi: 10.1124/jpet.107.128785. Epub 2007 Sep 28.
The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose 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-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C(max) values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and approximately 50% for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after multiple dosing.
3,4-(±)-亚甲基二氧甲基苯丙胺（摇头丸，MDMA）的5-羟色胺能神经毒性似乎取决于全身代谢，因为将MDMA直接注射到大脑中无法重现这种神经毒性。MDMA经去亚甲基化生成儿茶酚代谢产物N-甲基-α-甲基多巴胺（N-Me-α-MeDA）。N-Me-α-MeDA的硫醚（谷胱甘肽和N-乙酰半胱氨酸）代谢产物具有神经毒性，皮下注射MDMA后可在大鼠脑中检测到。由于摇头丸派对期间吸毒通常是多次服用MDMA，因此本研究旨在确定多次服用MDMA对大鼠脑中神经毒性硫醚代谢产物浓度的影响。每隔12小时皮下注射一次MDMA（20mg/kg），共注射四次，导致纹状体透析液中N-Me-α-MeDA硫醚代谢产物显著蓄积。5-(谷胱甘肽-S-基)-N-Me-α-MeDA在第一次和第四次注射之间，曲线下面积（AUC）（0-300分钟）增加了33%，而2,5-双-(谷胱甘肽-S-基)-N-Me-α-MeDA则基本翻倍。同样，5-(N-乙酰半胱氨酸-S-基)-N-Me-α-MeDA（35%）和2,5-双-(N-乙酰半胱氨酸-S-基)-N-Me-α-MeDA（85%）的AUC（0-300分钟）增加反映了硫醚氨酸代谢产物的蓄积，这可能是因为它们的消除过程变得饱和。实际上，5-(N-乙酰半胱氨酸-S-基)-N-Me-α-MeDA和双-(N-乙酰半胱氨酸-S-基)-N-Me-α-MeDA的消除半衰期在第一次和第三次给药之间分别增加了5成和近3成。最后，虽然每次注射后单硫醚结合物的C(max)值基本不变，但在第一次和第四次注射之间，2,5-双-(谷胱甘肽-S-基)-N-Me-α-MeDA和2,5-双-(N-乙酰半胱氨酸-S-基)-N-Me-α-MeDA的值分别增加了38%和近5成。数据表明，多次给药后MDMA的神经毒性代谢产物可能在脑中蓄积。
