Involvement of the Pyrilamine Transporter, a Putative Organic Cation Transporter, in Blood-Brain Barrier Transport of Oxycodone

• DOI: 10.1124/dmd.108.022087
• Publication Date: 2008-07-08T00:33:23Z
• Authors: Takashi Okura; Asami Hattori; Yusuke Takano; Takenori Sato; Margareta Hammarl...; Tetsuya Terasaki; Yoshiharu Deguchi
• Keywords: Pyrilamine; Protonophore; Bumetanide; Tetraethylammonium; Tetraethylammonium chloride

The purpose of this study was to characterize blood-brain barrier (BBB) transport oxycodone, a cationic opioid agonist, via the pyrilamine transporter, putative organic cation using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13). Oxycodone and [³H]pyrilamine were both transported into TR-BBB13 in temperature- concentration-dependent manner with <i>K</i>_m values 89 28 μM, respectively. initial uptake oxycodone significantly enhanced by preloading vice versa. Furthermore, mutual inhibition suggests that common mechanism is involved their transport. Transport substrates inhibited type II cations (quinidine, verapamil, amantadine), but not classic transporter (OCT) and/or inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridinium, corticosterone), OCTN1 (ergothioneine) OCTN2 (l-carnitine), or anions. metabolic (rotenone sodium azide) insensitive extracellular membrane potential for substrates. increased at alkaline pH decreased presence protonophore (carbonyl cyanide-<i>p</i>-trifluoromethoxyphenylhydrazone). Intracellular acidification induced ammonium chloride uptakes, suggesting driven an oppositely directed proton gradient. measured situ perfusion perfusate pyrilamine. These results suggest least partly mediated pyrilamine, energy-dependent, proton-coupled antiporter.