Department of Clinical Pharmacology, University Medical Center, Georg-August-University, Göttingen, Germany.
Clin Pharmacol Ther. 2011 Jul;90(1):143-50. doi: 10.1038/clpt.2011.56. Epub 2011 May 11.
We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.
我们研究了曲马多或其活性代谢物 O-去甲基曲马多是否为有机阳离子转运蛋白 OCT1 的底物，以及 OCT1 多态性是否影响曲马多和 O-去甲基曲马多的药代动力学。曲马多在平行人工膜透过性测定（PAMPA）中显示出很高的通透性。OCT1 过表达后，HEK293 细胞中曲马多的摄取没有变化，健康志愿者血浆中曲马多的浓度与其 OCT1 基因型无关。相比之下，O-去甲基曲马多的膜通透性较低，OCT1 过表达使 O-去甲基曲马多的摄取增加了 2.4 倍。这种摄取的增加被 OCT1 抑制剂逆转，当功能丧失的 OCT1 变体过表达时则不存在。携带功能丧失 OCT1 多态性的志愿者的 O-去甲基曲马多血浆浓度明显升高（P=0.002，n=41），瞳孔缩小（一种阿片样效应的替代标志物）明显延长（P=0.005，n=24）。总之，OCT1 多态性影响 O-去甲基曲马多的药代动力学，可能通过影响其进入肝细胞的摄取，从而调节曲马多治疗的疗效。
