Heydari A, Yeo K Rowland, Lennard M S, Ellis S W, Tucker G T, Rostami-Hodjegan A
Division of Clinical Sciences (South), University of Sheffield, UK.
Drug Metab Dispos. 2004 Nov;32(11):1213-7. doi: 10.1124/dmd.104.001180. Epub 2004 Aug 24.
The potency of methylenedioxymethamphetamine (MDMA) as a mechanism-based inhibitor of CYP2D6 has been defined using microsomes prepared from yeast expressing the enzyme and from three human livers. The inhibitory effect was increased by preincubation through formation of a metabolic intermediate complex. Inactivation parameters (kinact and KI), defined with respect to the O-demethylation of dextromethorphan, were 0.29 +/- 0.03 (S.E.) min(-1) and 12.9 +/- 3.6 (S.E.) microM for yeast-expressed CYP2D6, and 0.26 +/- 0.02 min(-1) and 14.4 +/- 2.5 microM, 0.15 +/- 0.01 min(-1) and 8.8 +/- 2.6 microM, and 0.12 +/- 0.05 min(-1) and 45.3 +/- 32.1 microM for the liver microsomal preparations. The rate of inactivation of CYP2D6 by MDMA decreased when quinidine, a competitive inhibitor of CYP2D6, was added to the primary incubation mixture. However, inactivation was unaffected by the addition of glutathione. The results indicate that MDMA is a potent mechanism-based inhibitor of CYP2D6, with implications for understanding its in vivo disposition and drug interaction potential.
已利用表达该酶的酵母制备的微粒体以及来自三个人类肝脏的微粒体，确定了亚甲基二氧甲基苯丙胺（摇头丸，MDMA）作为CYP2D6基于机制的抑制剂的效力。通过形成代谢中间复合物，预孵育可增强抑制作用。针对右美沙芬的O-去甲基化定义的失活参数（kinact和KI），对于酵母表达的CYP2D6分别为0.29±0.03（标准误）min⁻¹和12.9±3.6（标准误）μM，对于肝脏微粒体制剂分别为0.26±0.02 min⁻¹和14.4±2.5 μM、0.15±0.01 min⁻¹和8.8±2.6 μM以及0.12±0.05 min⁻¹和45.3±32.1 μM。当向初次孵育混合物中加入CYP2D6的竞争性抑制剂奎尼丁时，MDMA对CYP2D6的失活速率降低。然而，加入谷胱甘肽对失活没有影响。结果表明，MDMA是一种强效的基于机制的CYP2D6抑制剂，这对于理解其体内处置和药物相互作用潜力具有重要意义。
