Ketabi-Kiyanvash Nahal, Weiss Johanna, Haefeli Walter Emil, Mikus Gerd
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Bergheimer Strasse 58, D-69115 Heidelberg, Germany.
Addict Biol. 2003 Dec;8(4):413-8. doi: 10.1080/13556210310001646475.
There are increasing numbers of deaths related to taking MDMA, MDE and PMA reported where the deceased typically took several different drugs with these compounds. Hence, mutual modulation of the pharmacokinetics in drug combinations with "ecstasy" might be a risk factor for "ecstasy"-related morbidity. Regarding potential drug - drug interactions, there are no data evaluating a possible contribution of the multidrug resistance transporter P-glycoprotein (Pgp) in contrast to the cytochrome P450 enzyme system. Therefore, individual "ecstasy" compounds have been tested for their ability to interact with Pgp using a fluorometric calcein assay as a model for Pgp inhibition in porcine kidney epithelial cells with overexpression of human Pgp (L-MDR1). All three compounds increased calcein retention in L-MDR1 cells in a concentration-dependent manner, with MDE being the most potent and MDMA the weakest Pgp inhibitor. The effective concentrations were 1 - 3 orders of magnitude higher than plasma concentrations observed in vivo, suggesting that these compounds are only weak inhibitors of Pgp, which is unlikely to influence the access of other compounds to the brain. However, it cannot be excluded that co-administration of Pgp inhibitors such as ritonavir or paroxetine could increase MDMA, MDE and PMA bioavailability and also enhance brain entry leading to severe side effects.
据报道，与服用摇头丸（MDMA）、3,4-亚甲基二氧乙基苯丙胺（MDE）和对甲基氨基苯甲酸丙酯（PMA）相关的死亡人数不断增加，死者通常同时服用几种不同的含这些化合物的毒品。因此，与“摇头丸”组合用药时药代动力学的相互调节可能是与“摇头丸”相关发病的一个风险因素。关于潜在的药物相互作用，与细胞色素P450酶系统相比，没有数据评估多药耐药转运蛋白P-糖蛋白（Pgp）的可能作用。因此，使用荧光素酶测定法作为在过表达人Pgp（L-MDR1）的猪肾上皮细胞中Pgp抑制模型，测试了各个“摇头丸”化合物与Pgp相互作用的能力。所有三种化合物均以浓度依赖性方式增加了L-MDR1细胞中荧光素酶的保留，其中MDE是最有效的Pgp抑制剂，而MDMA是最弱的Pgp抑制剂。有效浓度比体内观察到的血浆浓度高1至3个数量级，这表明这些化合物只是Pgp的弱抑制剂，不太可能影响其他化合物进入大脑。然而，不能排除同时服用利托那韦或帕罗西汀等Pgp抑制剂会增加MDMA、MDE和PMA的生物利用度，并增强大脑进入，从而导致严重的副作用。
