Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
J Pharmacol Exp Ther. 2011 Jul;338(1):310-7. doi: 10.1124/jpet.111.180612. Epub 2011 Apr 14.
The baboon is potentially an attractive animal for modeling 3,4-methylenedioxymethamphetamine (MDMA) effects in humans. Baboons self-administer MDMA, are susceptible to MDMA neurotoxicity, and are suitable for positron emission tomography, the method most often used to probe for MDMA neurotoxicity in humans. Because pharmacokinetic equivalence is a key feature of a good predictive animal model, we compared the pharmacokinetics of MDMA in baboons and humans. Baboons were trained to orally consume MDMA. Then, pharmacokinetic profiles of MDMA and its major metabolites were determined after various oral MDMA doses using the same analytical method recently used to perform similar studies in humans. Results indicate that MDMA pharmacokinetics after oral ingestion differ markedly between baboons and humans. Baboons had little or no MDMA in their plasma but had high plasma concentrations of 3,4-dihydroxymethamphetamine (HHMA), pointing to much more extensive first-pass metabolism of MDMA in baboons than in humans. Other less prominent differences included less O-methylation of HHMA to 4-hydroxy-3-methoxymethamphetamine, greater N-demethylation of MDMA to 3,4-methylenedioxyamphetamine, and a shorter half-life of HHMA in the baboon. To our knowledge, this is the first study to characterize MDMA metabolism and disposition in the baboon. Differences in MDMA pharmacokinetics between baboons and humans suggest that the baboon may not be ideal for modeling human MDMA exposure. However, the unusually rapid conversion of MDMA to HHMA in the baboon may render this animal uniquely useful for clarifying the relative role of the parent compound (MDMA) versus metabolites (particularly HHMA) in the biological actions of MDMA.
食蟹猴可能是一种很有吸引力的动物模型，可以用来模拟 3,4-亚甲基二氧甲基苯丙胺（MDMA）对人类的影响。食蟹猴会自行摄入 MDMA，易发生 MDMA 神经毒性，并且适合正电子发射断层扫描（PET），这是最常用于探测人类 MDMA 神经毒性的方法。由于药代动力学等效性是一个良好的预测动物模型的关键特征，我们比较了 MDMA 在食蟹猴和人类中的药代动力学。我们训练食蟹猴口服摄入 MDMA。然后，使用最近用于在人类中进行类似研究的相同分析方法，在不同的口服 MDMA 剂量后，确定 MDMA 及其主要代谢物的药代动力学特征。结果表明，食蟹猴口服摄入后的 MDMA 药代动力学在食蟹猴和人类之间有明显差异。食蟹猴的血浆中几乎没有 MDMA，但 HHMA（3,4-二羟基甲基苯丙胺）的血浆浓度很高，这表明 MDMA 在食蟹猴中的首过代谢比在人类中更为广泛。其他不太明显的差异包括 HHMA 对 4-羟基-3-甲氧基甲基苯丙胺的 O-甲基化程度较低、MDMA 对 3,4-亚甲基二氧基苯丙胺的 N-去甲基化程度较大，以及 HHMA 在食蟹猴体内的半衰期较短。据我们所知，这是首次在食蟹猴中描述 MDMA 代谢和分布的研究。食蟹猴和人类之间 MDMA 药代动力学的差异表明，食蟹猴可能不适合模拟人类 MDMA 暴露。然而，MDMA 在食蟹猴体内迅速转化为 HHMA 的特点可能使这种动物在阐明母体化合物（MDMA）与代谢物（特别是 HHMA）在 MDMA 生物学作用中的相对作用方面具有独特的价值。
