Salonen Jarmo S, Nyman Leena, Boobis Alan R, Edwards Robert J, Watts Patricia, Lake Brian G, Price Roger J, Renwick Anthony B, Gómez-Lechón Maria-Jose, Castell José V, Ingelman-Sundberg Magnus, Hidestrand Mats, Guillouzo Andre, Corcos Laurent, Goldfarb Peter S, Lewis David F V, Taavitsainen Päivi, Pelkonen Olavi
Orion Pharma Preclinical and Clinical R&D, Turku, Finland.
Drug Metab Dispos. 2003 Sep;31(9):1093-102. doi: 10.1124/dmd.31.9.1093.
Selegiline was used as a model compound in a project aimed at comparing, evaluating, and integrating different in vitro approaches for the prediction of cytochrome p450 (p450)-catalyzed hepatic drug metabolism in humans (EUROCYP). Metabolic predictions were generated using homology modeling, cDNA-expressed p450 enzymes, human liver microsomes, primary cultured human hepatocytes, and precision-cut human liver slices. All of the in vitro systems correctly indicated the formation of two dealkylated metabolites, desmethylselegiline and methamphetamine. The metabolic instability of selegiline was demonstrated by all of the in vitro systems studied. Estimates of clearance varied from 16 l/h to 223 l/h. With the exception of one approach, all systems underpredicted the in vivo clearance in humans (236 l/h). Despite this, all approaches successfully classified selegiline as a high clearance compound. Homology modeling suggested the participation of CYP2B6 in the demethylation of selegiline and of CYP2D6 in the depropargylation of the drug. Studies with recombinant expressed enzymes and with human hepatic microsomal fraction supported the involvement of CYP2B6 but not of CYP2D6. These techniques also suggested the involvement of CYP1A2, CYP2C8, and CYP2C19 in the biotransformation of selegiline. In vitro, CYP2B6 was the most active form of p450 involved in selegiline metabolism. Metabolism by several enzymes operating in parallel implies a low interaction potential for the drug. None of the techniques alone was able to predict all aspects of the metabolic and kinetic behavior of selegiline in vivo. However, when used as an integrated package, all significant characteristics were predictable.
司来吉兰被用作一个项目中的模型化合物，该项目旨在比较、评估和整合不同的体外方法，以预测细胞色素P450（P450）催化的人体肝脏药物代谢（EUROCYP）。使用同源建模、cDNA表达的P450酶、人肝微粒体、原代培养的人肝细胞和精密切割的人肝切片进行代谢预测。所有体外系统均正确显示了两种脱烷基代谢物去甲基司来吉兰和甲基苯丙胺的形成。所研究的所有体外系统均证明了司来吉兰的代谢不稳定性。清除率估计值在16升/小时至223升/小时之间。除一种方法外，所有系统均低估了人体的体内清除率（236升/小时）。尽管如此，所有方法均成功将司来吉兰归类为高清除率化合物。同源建模表明CYP2B6参与司来吉兰的去甲基化，而CYP2D6参与该药物的去炔丙基化。对重组表达酶和人肝微粒体组分的研究支持CYP2B6的参与，但不支持CYP2D6的参与。这些技术还表明CYP1A2、CYP2C8和CYP2C19参与司来吉兰的生物转化。在体外，CYP2B6是参与司来吉兰代谢的最活跃的P450形式。几种酶并行作用的代谢意味着该药物的相互作用潜力较低。单独一种技术均无法预测司来吉兰在体内的代谢和动力学行为的所有方面。然而，当作为一个综合包使用时，所有重要特征都是可预测的。
