title: Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone.
abstract: The purpose of this study was to characterize blood-brain barrier (BBB) transport of oxycodone, a cationic opioid agonist, via the pyrilamine transporter, a putative organic cation transporter, using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13). Oxycodone and [3H]pyrilamine were both transported into TR-BBB13 cells in a temperature- and concentration-dependent manner with Km values of 89 and 28 microM, respectively. The initial uptake of oxycodone was significantly enhanced by preloading with pyrilamine and vice versa. Furthermore, mutual uptake inhibition by oxycodone and pyrilamine suggests that a common mechanism is involved in their transport. Transport of both substrates was inhibited by type II cations (quinidine, verapamil, and amantadine), but not by classic organic cation transporter (OCT) substrates and/or inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridinium, and corticosterone), substrates of OCTN1 (ergothioneine) and OCTN2 (L-carnitine), or organic anions. The transport was inhibited by metabolic inhibitors (rotenone and sodium azide) but was insensitive to extracellular sodium and membrane potential for both substrates. Furthermore, the transport of both substrates was increased at alkaline extracellular pH and decreased in the presence of a protonophore (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone). Intracellular acidification induced with ammonium chloride enhanced the uptakes, suggesting that the transport is driven by an oppositely directed proton gradient. The brain uptake of oxycodone measured by in situ rat brain perfusion was increased in alkaline perfusate and was significantly inhibited by pyrilamine. These results suggest that blood-brain barrier transport of oxycodone is at least partly mediated by a common transporter with pyrilamine, and this transporter is an energy-dependent, proton-coupled antiporter.
authors.affiliation: Department of Drug Disposition and Pharmacokinetics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.forename: Asami
authors.initials: A
authors.lastname: Hattori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takano
authors.forename: Takenori
authors.initials: T
authors.lastname: Sato
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D020869:Gene Expression Profiling; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics; D010098:Oxycodone / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D011738:Pyrilamine / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium
chemical_list: D004337:Drug Carriers; D006634:Histamine H1 Antagonists; D027701:Organic Cation Transport Proteins; D014316:Tritium; D010098:Oxycodone; D011738:Pyrilamine