Bomsien Stephanie, Skopp Gisela
Institute of Legal Medicine and Traffic Medicine, Ruprecht-Karls University, Vossstr. 2, 69115, Heidelberg, Germany.
Eur J Clin Pharmacol. 2007 Sep;63(9):821-7. doi: 10.1007/s00228-007-0327-z. Epub 2007 Jun 28.
The aim of this study was to assess the drug interaction potential of psychotropic medication on methadone N-demethylation using cDNA-expressed cytochrome P450 CYP enzymes.
Methadone was incubated with various drugs (n = 10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to screen for their inhibition potency. The nature of enzyme selective activity for inhibition was further investigated for potent inhibitors. To test for a mechanism-based component in inhibition, all substances were tested with preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentration was determined by liquid chromatography/tandem mass spectrometry following liquid/liquid extraction.
Formation of EDDP was catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was preferentially inhibited by amitriptyline, buprenorphine, methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed a mechanism-based inhibition of CYP3A4.
Amitriptyline, MDMA and zolpidem are likely to slow down conversion of methadone and to increase its area under the curve (AUC). A consideration of the in vitro evidence of drug-methadone interactions should help to improve patient care during methadone maintenance treatment.
本研究旨在利用cDNA表达的细胞色素P450 CYP酶评估精神药物对美沙酮N-去甲基化的药物相互作用潜力。
将美沙酮与多种药物（n = 10）以及cDNA表达的CYP3A4、CYP2D6、CYP2B6、CYP2C19和CYP1A2酶一起孵育，以筛选它们的抑制效力。对强效抑制剂进一步研究其抑制的酶选择性活性的性质。为了测试抑制中基于机制的成分，所有物质都进行了预孵育和未预孵育测试。液/液萃取后，通过液相色谱/串联质谱法测定2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）的浓度。
EDDP的形成由CYP3A4、CYP2D6和CYP2C19催化。美沙酮的N-去甲基化优先被阿米替林、丁丙诺啡、亚甲基二氧甲基苯丙胺（摇头丸）和唑吡坦抑制。阿米替林和丁丙诺啡都是CYP3A4的强效可逆抑制剂。同样，阿米替林和摇头丸被鉴定为CYP2D6的抑制剂。唑吡坦显示出对CYP3A4的基于机制的抑制作用。
阿米替林、摇头丸和唑吡坦可能会减缓美沙酮的转化并增加其曲线下面积（AUC）。考虑药物与美沙酮相互作用的体外证据应有助于改善美沙酮维持治疗期间的患者护理。
