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Research ArticleArticle

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

Takashi Okura, Asami Hattori, Yusuke Takano, Takenori Sato, Margareta Hammarlund-Udenaes, Tetsuya Terasaki and Yoshiharu Deguchi
Drug Metabolism and Disposition October 2008, 36 (10) 2005-2013; DOI: https://doi.org/10.1124/dmd.108.022087
Takashi Okura
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Asami Hattori
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Yusuke Takano
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Takenori Sato
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Margareta Hammarlund-Udenaes
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Tetsuya Terasaki
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Yoshiharu Deguchi
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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 μM, 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.

Footnotes

  • This work was supported in part by a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Young Scientists provided by the Ministry of Education, Culture, Sports, Science and Technology.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022087.

  • ABBREVIATIONS: BBB, blood-brain barrier; GLUT, glucose transporter; MCT, monocarboxylate transporter; LAT, large neutral amino acid transporter; OAT/Oat, organic anion transporter 3; OATP/Oatp, organic anion transport polypeptide; OCT, organic cation transporter; MATE, multidrug and toxin extrusion; TR-BBB13 cells, conditionally immortalized rat brain capillary endothelial cells; CNS, central nervous system; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; pHi, intracellular pH; HPLC, high-performance liquid chromatography; PCR, polymerase chain reaction; r, rat; RT, reverse transcriptase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; B/P, blood/perfusion.

    • Received April 25, 2008.
    • Accepted July 3, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
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Research ArticleArticle

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

Takashi Okura, Asami Hattori, Yusuke Takano, Takenori Sato, Margareta Hammarlund-Udenaes, Tetsuya Terasaki and Yoshiharu Deguchi
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2005-2013; DOI: https://doi.org/10.1124/dmd.108.022087

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Research ArticleArticle

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

Takashi Okura, Asami Hattori, Yusuke Takano, Takenori Sato, Margareta Hammarlund-Udenaes, Tetsuya Terasaki and Yoshiharu Deguchi
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2005-2013; DOI: https://doi.org/10.1124/dmd.108.022087
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