Fonsart Julien, Menet Marie-Claude, Debray Marcel, Hirt Déborah, Noble Florence, Scherrmann Jean-Michel, Declèves Xavier
Université Paris Descartes, Faculté de Pharmacie, Paris F-75006, France.
Toxicol Appl Pharmacol. 2009 Dec 15;241(3):339-47. doi: 10.1016/j.taap.2009.09.008. Epub 2009 Sep 23.
The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in recent years; it can lead to life-threatening hyperthermia and serotonin syndrome. Human and rodent males appear to be more sensitive to acute toxicity than are females. MDMA is metabolized to five main metabolites by the enzymes CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA disposition in male and female rats by measuring the plasma and urine concentrations of MDMA and its metabolites using a validated LC-MS method. MDA AUC(last) and C(max) were 1.6- to 1.7-fold higher in males than in females given MDMA (5 mg/kg sc), while HMMA C(max) and AUC(last) were 3.2- and 3.5-fold higher, respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA was 2.2-fold higher. MDMA AUC(last) and t(1/2) were 50% higher in females given MDMA (1 mg/kg iv). MDA C(max) and AUC(last) were 75-82% higher in males, with a 2.8-fold higher metabolic index. Finally, the AUC(last) of MDA was 0.73-fold lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA at steady-state were similar in the two sexes. These data strongly suggest that differences in the N-demethylation of MDMA to MDA are major influences on the MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed to significantly more toxic MDA, which could explain previously reported sexual dysmorphism in the acute effects and toxicity of MDMA in rats.
近年来，3,4-亚甲基二氧甲基苯丙胺（摇头丸，MDMA）的使用呈上升趋势；它可导致危及生命的高热和血清素综合征。人类和啮齿类雄性动物似乎比雌性对急性毒性更敏感。MDMA可通过细胞色素P450 1A2（CYP1A2）、细胞色素P450 2D（CYP2D）和儿茶酚-O-甲基转移酶（COMT）代谢为五种主要代谢产物。目前，关于MDMA及其代谢产物药代动力学的性别差异知之甚少。因此，我们通过使用经过验证的液相色谱-质谱法测量MDMA及其代谢产物的血浆和尿液浓度，分析了雄性和雌性大鼠体内MDMA的处置情况。给予MDMA（5毫克/千克，皮下注射）后，雄性大鼠中3,4-亚甲基二氧苯丙胺（MDA）的曲线下面积（AUC(last)）和峰浓度（C(max)）比雌性高1.6至1.7倍，而4-羟基-3,4-亚甲基二氧苯丙胺（HMMA）的C(max)和AUC(last)分别高3.2倍和3.5倍。MDMA的肾脏清除率在雄性中高1.26倍，MDA的肾脏清除率高2.2倍。给予MDMA（1毫克/千克，静脉注射）后，雌性大鼠中MDMA的AUC(last)和半衰期（t(1/2)）高50%。雄性大鼠中MDA的C(max)和AUC(last)高75 - 82%，代谢指数高2.8倍。最后，给予1毫克/千克静脉注射MDA后，雄性大鼠中MDA的AUC(last)低0.73倍。MDMA和MDA在稳态时的分布容积在两性中相似。这些数据有力地表明，MDMA向MDA的N-去甲基化差异是雄性和雌性大鼠中MDMA和MDA药代动力学的主要影响因素。因此，雄性接触到的毒性显著更高的MDA，这可以解释先前报道的大鼠中MDMA急性效应和毒性方面的性别差异。
