Proton-Coupled Organic Cation Antiporter-Mediated Uptake of Apomorphine Enantiomers in Human Brain Capillary Endothelial Cell Line hCMEC/D3
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- Okura Takashi
- Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University
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- Higuchi Kei
- Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University
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- Kitamura Atsushi
- Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University
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- Deguchi Yoshiharu
- Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University
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R(−)-Apomorphine is a dopamine agonist used for rescue management of motor function impairment associated with levodopa therapy in Parkinson’s disease patients. The aim of this study was to examine the role of proton-coupled organic cation antiporter in uptake of R(−)-apomorphine and its S-enantiomer in human brain, using human endothelial cell line hCMEC/D3 as a model. Uptake of R(−)- or S(+)-apomorphine into hCMEC/D3 cells was measured under various conditions to evaluate its time-, concentration-, energy- and ion-dependency. Inhibition by selected organic cations was also examined. Uptakes of both R(−)- and S(+)-apomorphine increased with time. The initial uptake velocities of R(−)- and S(+)-apomorphine were concentration-dependent, with similar Km and Vmax values. The cell-to-medium (C/M) ratio of R(−)-apomorphine was significantly reduced by pretreatment with sodium azide, but was not affected by replacement of extracellular sodium ion with N-methylglucamine or potassium. Intracellular alkalization markedly reduced the uptake, while intracellular acidification increased it, suggesting that the uptake is driven by an oppositely directed proton gradient. The C/M ratio was significantly decreased by amantadine, verapamil, pyrilamine and diphenhydramine (substrates or inhibitors of proton-coupled organic cation antiporter), while tetraethylammonium (substrate of organic cation transporters (OCTs)) and carnitine (substrate of carnitine/organic cation transporter 2; (OCTN2)) had no effect. R(−)-Apomorphine uptake was competitively inhibited by diphenhydramine. Our results indicate that R(−)-apomorphine transport in human blood–brain barrier (BBB) model cells is similar to S(+)-apomorphine uptake. The transport was dependent on an oppositely directed proton gradient, but was sodium- or membrane potential-independent. The transport characteristics were consistent with involvement of the previously reported proton-coupled organic cation antiporter.
収録刊行物
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- Biological & Pharmaceutical Bulletin
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Biological & Pharmaceutical Bulletin 37 (2), 286-291, 2014
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204633711872
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- NII論文ID
- 130003382121
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- NII書誌ID
- AA10885497
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- COI
- 1:STN:280:DC%2BC2c7ovVeisA%3D%3D
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- ISSN
- 13475215
- 09186158
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- NDL書誌ID
- 025172884
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- PubMed
- 24257040
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- 抄録ライセンスフラグ
- 使用不可