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Drug Metabolism and Disposition Fast Forward
First published on July 7, 2008; DOI: 10.1124/dmd.108.022087
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Received for publication April 28, 2008.
Revised July 2, 2008.
Accepted for publication July 3, 2008.

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

Takashi Okura 1, Asami Hattori 1, Yusuke Takano 1, Takenori Sato 1, Margareta Hammarlund-Udenaes 2, Tetsuya Terasaki 3, Yoshiharu Deguchi 1*

1 School of Pharmaceutical Sciences, Teikyo University 2 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 3 Graduate School of Pharmaceutical Sciences, Tohoku University

* Address correspondence to: E-mail: deguchi{at}pharm.teikyo-u.ac.jp

Abstract

The purpose of this study is 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 µM and 28 µM, respectively. The initial uptake of oxycodone was significantly enhanced by preloading with pyrilamine, and vice versa. Further, 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, amantadine), but not by classic OCT substrates and/or inhibitors (TEA, MPP, corticosterone), substrates of OCTN1 (ergothioneine) and OCTN2 (L-carnitine), or organic anions. The transport was inhibited by metabolic inhibitors (rotenone, sodium azide), but was insensitive to extracellular sodium and membrane potential for both substrates. Further, the transport of both substrates was increased at alkaline extracellular pH, and decreased in the presence of a protonophore (FCCP). 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 BBB transport of oxycodone is at least partly mediated by a common transporter with pyrilamine, and this transporter is an energy-dependent, proton-coupled antiporter.


Key words: blood-brain barrier, blood-CNS transport, drug transport, membrane transport, organic cation transport, transporters




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