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1.
論文 |
増尾, 友佑 ; Masuo, Yusuke
概要:
金沢大学医薬保健研究域薬学系<br />肝消失型薬物の一部は、血漿中からの消失が慢性腎障害時に遅延する。そこで、OATP1B1阻害作用を有する生体内化合物を探索したところ、6-OH indoleはOATP1B1を阻害した。血漿中6-OH i
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ndole濃度は、腎障害患者において、正常腎機能患者よりも血漿中濃度が高かった。この化合物によるOATP1B1阻害作用は持続的であり、プレインキュベーション時のみに添加した際にも阻害作用を有した。さらに、本化合物は、ヒト初代培養肝細胞でestrone 3-sulfateの細胞内取り込みを阻害した。本化合物は、慢性腎障害時に血液中に蓄積してOATP1B1の機能阻害を引き起こすことが示唆された。<br />Several uremic tocxins have been proposed to inhibit hepatic uptake transporters. The purpose of this study is to find possible inhibition of OATP1B1 by newly identified uremic toxins, 6-OH indole. 6-OH indole inhibited OATP1B1-mediated uptake of [3H]estrone sulfate in HEK293/OATP1B1 cells. Plasma concentration of 6-OH indole was higher in patients with severe renal failure than that in patients without renal failure. The inhibition pattern of OATP1B1 by 6-OH indole was long-lasting, since its inhibition was maintained after 6-OH indole was washed out. Also, 6-OH indole inhibited uptake of estrone sulfate in primary cultured hepatocytes without changing mRNA expression of OATP1B1. These results suggest that increase of 6-OH indole in plasma during CKD could at least partially explain the delayed elimination of OATP1B1 substrate drugs.<br />研究課題/領域番号:16K18934, 研究期間(年度):2016-04-01 - 2018-03-31
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2.
論文 |
増尾, 友佑 ; Masuo, Yusuke
概要:
金沢大学医薬保健研究域薬学系<br />一部の肝消失型薬物は、血中消失が慢性腎障害患者で遅延し、この原因として患者血漿中で蓄積する一部の尿毒素による肝膜輸送体のdirect inhibitionが報告されているが、他の尿毒素による阻害やdi
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rect inhibition以外の作用は未解明である。本研究では、p-cresyl sulfateによる肝膜輸送体OATP1B1のdirect inhibitionとindoxyl sulfateによるOATP1B1のlong-lasting inhibitionを明らかにした。本研究で明らかになった阻害作用は、慢性腎障害時におけるOATP1B1基質薬の血中消失の遅延を一部説明しうるものである。<br />Several uremic toxins have been proposed to inhibit hepatic uptake transporters. The purpose is to clarify possible long-lasting inhibition of OATP1B1 by uremic toxins. OATP1B1-mediated uptake of [3H]estrone sulfate (E3S) was examined after co-incubation or preincubation with uremic toxins in HEK293/OATP1B1 cells and primary cultured human hepatocytes. Among 21 uremic toxins, indoxyl sulfate (IS), CMPF and p-cresyl sulfate directly inhibited OATP1B1 mediated-uptake of E3S, but only IS exhibited inhibitory effect even after preincubation. Such inhibition of E3S uptake by preincubation with IS was more remarkable than that by its co-incubation, and observed in preincubation time- and concentration-dependent manners. Preincubation with IS also decreased uptake of E3S in human hepatocytes in primary culture. Overall, the long-lasting inhibition in the presence of IS could at least partially explain the delayed elimination of OATP1B1 substrate drugs during severe renal failure.<br />研究課題/領域番号:26860099, 研究期間(年度):2014-04-01 - 2016-03-31
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