Kitamura Atsushi, Higuchi Kei, Okura Takashi, Deguchi Yoshiharu
Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Itabashi, Tokyo, 173-8605, Japan.
J Pharm Sci. 2014 Oct;103(10):3335-41. doi: 10.1002/jps.24129. Epub 2014 Aug 29.
Tramadol is a centrally acting analgesic whose action is mediated by both agonistic activity at opioid receptors and inhibitory activity on neuronal reuptake of monoamines. The purpose of this study was to characterize the blood-brain barrier (BBB) transport of tramadol by means of microdialysis studies in rat brain and in vitro studies with human immortalized brain capillary endothelial cells (hCMEC/D3). The Kp,uu,brain value of tramadol determined by rat brain microdialysis was greater than unity, indicating that tramadol is actively taken up into the brain across the BBB. Tramadol was transported into hCMEC/D3 cells in a concentration-dependent manner. The uptake was inhibited by type II cations (pyrilamine, verapamil, etc.), but not by substrates of organic cation transporter OCTs or OCTN2. It was also inhibited by a metabolic inhibitor but was independent of extracellular sodium or membrane potential. The uptake was altered by changes of extracellular pH, and by ammonium chloride-induced intracellular acidification, suggesting that transport of tramadol is driven by an oppositely directed proton gradient. Thus, our in vitro and in vivo results suggest that tramadol is actively transported, at least in part, from blood to the brain across the BBB by proton-coupled organic cation antiporter.
曲马多是一种中枢性镇痛药，其作用由阿片受体激动活性和对单胺类神经元再摄取的抑制活性介导。本研究的目的是通过大鼠脑微透析研究和用人永生化脑微血管内皮细胞（hCMEC/D3）进行的体外研究来表征曲马多的血脑屏障（BBB）转运。通过大鼠脑微透析测定的曲马多的Kp,uu,brain值大于1，表明曲马多通过血脑屏障被主动摄取到脑中。曲马多以浓度依赖性方式转运到hCMEC/D3细胞中。摄取受到II型阳离子（吡苄明、维拉帕米等）的抑制，但不受有机阳离子转运体OCTs或OCTN2底物的抑制。它也受到代谢抑制剂的抑制，但与细胞外钠或膜电位无关。摄取因细胞外pH值的变化以及氯化铵诱导的细胞内酸化而改变，这表明曲马多的转运由相反方向的质子梯度驱动。因此，我们的体外和体内结果表明，曲马多至少部分是通过质子偶联有机阳离子反向转运体从血液中主动转运穿过血脑屏障进入大脑的。
