Involvement of Specific Transport System on Uptake of Lactone Form of SN-38 in Human Intestinal Epithelial Cell Line Caco-2
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概要
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The aim of this study was to elucidate the characteristics of the transport of lactone and carboxylate forms of SN-38 (SN-38L and SN-38C, respectively), a metabolite of irinotecan hydrochloride (CPT-11), with the human intestinal epithelial cell line, Caco-2. We examined SN-38L and SN-38C uptake from the apical side into Caco-2, and the effects of various compounds on the uptake of SN-38L. SN-38L and SN-38C in the cells were determined by HPLC with a fluorescence detector. When either SN-38L (0.5 µM) or SN-38C (0.5 µM) was added extracellularly at 37°C, the accumulation of SN-38L into the cells was about 10-fold higher than that of SN-38C, suggesting a dominant role of the lactone form in the uptake of SN-38 into Caco-2. The accumulation of SN-38L in Caco-2 increased time-dependently up to 10 min at 37°C, whereas the accumulation markedly decreased at 4°C. The initial uptake rate of SN-38L approached saturation at high concentrations with Michaelis–Menten constant and ‘Hill coefficient,’ 2.84±1.00 μM and 2.13±1.14, respectively (mean±S.E.). The accumulation of SN-38L was markedly inhibited by baicalin, an active ingredient of a Chinese herbal medicine, Hange-Shashin-To, as well as CPT-11. The type of inhibition by baicalin was competitive. In contrast, concomitant sulfobromophthalein, taurocholate and estrone 3-sulfate significantly increased SN-38L uptake. These results suggest that apical uptake of SN-38 by Caco-2 is dominantly performed as a lactone form through a specific transporter, which is competitively inhibited by baicalin.
著者
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Ueno Yusuke
Department Of Macromolecular Science Graduate School Of Science Osaka University
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Okuda Masahiro
Department Of Anesthesiology Mie University School Of Medicine
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Matsuda Hiroko
Department Of Applied Chemistry Graduate School Of Engineering Tokyo University Of Agriculture And T
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Mizutani Hideki
Department Of Environmental And Molecular Medicine Mie University School Of Medicine
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Mizutani Hideki
Department Of Clinical Pharmacy And Biopharmaceutics Mie University Graduate School Of Medicine
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Iwamoto Takuya
Department of Clinical Pharmacy and Biopharmaceutics, Graduate School of Medicine, Mie University
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Iwamoto Takuya
Department of Advanced Science and Technology, Toyota Technological Institute, Nagoya 468-8511, Japan
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Matsuda Hiroko
Department of Clinical Pharmacy and Biopharmaceutics, Graduate School of Medicine, Mie University
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Mizutani Hideki
Department of Clinical Pharmacy and Biopharmaceutics, Graduate School of Medicine, Mie University
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Ueno Yusuke
Department of Clinical Pharmacy and Biopharmaceutics, Graduate School of Medicine, Mie University
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