Faculté de Pharmacie, Université Paris Descartes, Paris F-75006, France.
Toxicol Sci. 2010 Mar;114(1):38-47. doi: 10.1093/toxsci/kfp300. Epub 2009 Dec 14.
The pharmacokinetics of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) and its mains metabolites have never been modeled together. We therefore designed a model with which to analyze the pharmacokinetics of MDMA, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) and to test the effect of covariates like gender and body weight on the pharmacokinetics. Rats (18 males and 18 females) were given 1 mg/kg MDMA iv, and the concentrations of MDMA, MDA, and HMMA were measured by high-performance liquid chromatography-mass spectrometry. Another 30 rats (15 males) were given 1 mg/kg MDA, and MDA and HMA were measured. A population pharmacokinetic model was developed to describe the changes in MDMA, HMMA, MDA, and HMA concentrations over time and to estimate interanimal variability. The influence of gender was tested using a likelihood ratio test. Estimated exposures of males and females to MDMA and its metabolites were compared using the Wilcoxon nonparametric test. An integrated six-compartment model adequately described the data. MDMA (two compartments) was transformed irreversible to HMMA (one compartment) and MDA (two compartments), which then produced HMA (one compartment). All rate constants were first order. Females given MDMA had significantly smaller MDMA distribution volumes than males, and they converted less MDMA to MDA than did males. Our MDMA, MDA, HMA, and HMMA model is suitable for examining the relationship between drug concentrations and its pharmacological/toxicological effects. Male rats were exposed to significantly more MDA and HMA than were females, which could explain why males are more sensitive to MDMA toxic effects than females.
娱乐性药物 3,4-亚甲二氧基甲基苯丙胺（MDMA）及其主要代谢物的药代动力学从未被同时建模过。因此，我们设计了一个模型来分析 MDMA、3,4-亚甲二氧基苯丙胺（MDA）、4-羟基-3-甲氧基甲基苯丙胺（HMMA）和 4-羟基-3-甲氧基苯丙胺（HMA）的药代动力学，并检验性别和体重等协变量对药代动力学的影响。大鼠（18 只雄性和 18 只雌性）静脉注射 1mg/kg 的 MDMA，通过高效液相色谱-质谱法测定 MDMA、MDA 和 HMMA 的浓度。另外 30 只大鼠（15 只雄性）给予 1mg/kg 的 MDA，测定 MDA 和 HMA 的浓度。建立了一个群体药代动力学模型来描述 MDMA、HMMA、MDA 和 HMA 浓度随时间的变化，并估计动物间的变异性。性别影响通过似然比检验进行测试。使用 Wilcoxon 非参数检验比较雄性和雌性对 MDMA 及其代谢物的暴露程度。一个综合的六室模型很好地描述了数据。MDMA（两个室）不可逆地转化为 HMMA（一个室）和 MDA（两个室），然后 MDA 生成 HMA（一个室）。所有速率常数均为一级。给予 MDMA 的雌性大鼠的 MDMA 分布容积明显小于雄性大鼠，并且她们将 MDMA 转化为 MDA 的量也小于雄性大鼠。我们的 MDMA、MDA、HMA 和 HMMA 模型适合于研究药物浓度与其药理/毒理效应之间的关系。雄性大鼠暴露于 MDA 和 HMA 的量明显多于雌性大鼠，这可以解释为什么雄性大鼠对 MDMA 毒性效应比雌性大鼠更敏感。
