Kolbrich Erin A, Goodwin Robert S, Gorelick David A, Hayes Robert J, Stein Elliot A, Huestis Marilyn A
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
Ther Drug Monit. 2008 Jun;30(3):320-32. doi: 10.1097/FTD.0b013e3181684fa0.
This study examines the plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) in young adults for up to 143 hours after drug administration. Seventeen female and male participants (black, white, and Hispanic) received placebo, low (1.0 mg/kg), and high (1.6 mg/kg) oral MDMA doses (comparable to recreational doses) in a double-blind, randomized, balanced, within-subject design while residing on a closed research unit. Doses were separated by 1 week or more. A fully validated two-dimensional gas chromatography/mass spectrometry method simultaneously quantified MDMA, HMMA, MDA, and HMA. Calibration curves were MDA, 1 to 100 ng/mL; HMA, 2.5 to 100 ng/mL; and MDMA and HMMA, 2.5 to 400 ng/mL. Mean +/- standard deviation maximum plasma concentrations (C(max)) of 162.9 +/- 39.8 and 171.9 +/- 79.5 ng/mL were observed for MDMA and HMMA, respectively, after low-dose MDMA. After the high dose, mean MDMA Cmax significantly increased to 291.8 +/- 76.5 ng/mL, whereas mean HMMA C(max) was unchanged at 173.5 +/- 66.3 ng/mL. High intersubject variability in C(max) was observed. Mean MDA C(max) were 8.4 +/- 2.1 (low) and 13.8 +/- 3.8 (high) ng/mL. HMA Cmax were 3.5 +/- 0.4 and 3.9 +/- 0.9 ng/mL after the low and high doses, respectively. AUC infinity displayed similar trends to C(max), demonstrating nonlinear pharmacokinetics. Times of last plasma detection were generally HMA < MDA < MDMA < HMMA. Mean half-lives (t1/2) of MDMA, MDA, and HMMA were approximately 7 to 8 hours, 10.5 to 12.5 hours, and 11.5 to 13.5 hours, respectively. HMA t1/2 showed high variability. Mean MDMA volume of distribution was constant for low and high doses; clearance was significantly higher after the low dose. This study presents MDMA plasma pharmacokinetic data for the first time from blacks and females as well as measurement of HMMA and HMA concentrations after low and high MDMA doses and more frequent and extended plasma sampling than in prior studies.
本研究考察了3,4-亚甲基二氧甲基苯丙胺（摇头丸）及其代谢物4-羟基-3-甲氧基甲基苯丙胺（HMMA）、3,4-亚甲基二氧苯丙胺（MDA）和4-羟基-3-甲氧基苯丙胺（HMA）在年轻成人中的血浆药代动力学，给药后长达143小时进行观察。17名女性和男性参与者（黑人、白人和西班牙裔）在封闭的研究单位居住期间，采用双盲、随机、平衡的受试者内设计，接受安慰剂、低剂量（1.0mg/kg）和高剂量（1.6mg/kg）的口服摇头丸（与娱乐剂量相当）。各剂量之间间隔1周或更长时间。一种经过充分验证的二维气相色谱/质谱法同时对摇头丸、HMMA、MDA和HMA进行定量。校准曲线为：MDA，1至100ng/mL；HMA，2.5至100ng/mL；摇头丸和HMMA，2.5至400ng/mL。低剂量摇头丸给药后，摇头丸和HMMA的平均最大血浆浓度（C(max)）分别为162.9±39.8和171.9±79.5ng/mL。高剂量给药后，摇头丸的平均Cmax显著增加至291.8±76.5ng/mL，而HMMA的平均C(max)保持不变，为173.5±66.3ng/mL。观察到C(max)存在较高的个体间变异性。MDA的平均C(max)分别为8.4±2.1（低剂量）和13.8±3.8（高剂量）ng/mL。低剂量和高剂量给药后，HMA的Cmax分别为3.5±0.4和3.9±0.9ng/mL。AUC infinity呈现出与C(max)相似的趋势，表明存在非线性药代动力学。末次血浆检测时间一般为HMA＜MDA＜摇头丸＜HMMA。摇头丸、MDA和HMMA的平均半衰期（t1/2）分别约为7至8小时、10.5至12.5小时和11.5至13.5小时。HMA的t1/2显示出较高的变异性。低剂量和高剂量时摇头丸的平均分布容积恒定；低剂量后的清除率显著更高。本研究首次提供了黑人及女性的摇头丸血浆药代动力学数据，以及低剂量和高剂量摇头丸给药后HMMA和HMA浓度的测量结果，并且与之前的研究相比，血浆采样更频繁、时间更长。
