ヒグチ　ケイ   Higuchi Kei   樋口　慧    所属   東邦大学  薬学部 薬学科    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells.
掲載誌名	正式名：Journal of pharmaceutical sciences ISSNコード：0022-3549/1520-6017
掲載区分	国外
出版社	WILEY
巻・号・頁	106(9),pp.2576-2582
著者・共著者	Toshiki Kurosawa,Kei Higuchi,Takashi Okura,Kazumasa Kobayashi,Hiroyuki Kusuhara,Yoshiharu Deguchi
担当区分	2nd著者
発行年月	2017/09
概要	Varenicline is a selective partial α4β2 nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H+/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H+/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H+/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.
DOI	10.1016/j.xphs.2017.04.032
PMID	28454746