Lysosomal Trapping of Amodiaquine: Impact on Transport across Intestinal Epithelia Models
Lysosomal Trapping of Amodiaquine: Impact on Transport across Intestinal Epithelia Models
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DOI：
10.1002/bdd.616
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发表时间：
2008-09-01
影响因子：
2.1
通讯作者：
Ungell, Anna-Lena B.
中科院分区：
文献类型：
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作者：
Hayeshi, Rose;Masimirembwa, Collen;Ungell, Anna-Lena B.
亲脂性弱碱阿莫地喹是一种抗疟疾药物，已经使用了40多年。阿莫地喹的跨膜转运机制知之甚少。阿莫地喹在Caco-2细胞中的转运实验显示30%的低回收率和从顶室的快速消失。对结构上与阿莫地喹相似的化合物以及影响阿莫地喹非特异性结合或系统pH值的化合物进行了测试，以揭示这些观察结果背后的机制。氯喹和氯化铵增加阿莫地喹的跨单层渗透性，减少其在Caco-2细胞中的积聚，而BSA则无影响。氯喹和BSA降低塑料结合，而氯化铵没有影响。这表明阿莫地喹被困在酸性细胞区室如溶酶体中。阿莫地喹也被捕获在大鼠肠组织中。此外，从顶侧至基底侧方向的渗透性显著更高，表明大鼠组织的顶侧膜上的主动摄取。可以得出结论，阿莫地喹被困在酸性细胞室，由于其碱性和回收率可能会提高使用氯化铵，而不是BSA在运输实验。需要进一步的研究来证实阿莫地喹是否在肠道中被积极吸收。版权所有（C）2008约翰威利父子有限公司
The lipophilic weak base amodiaquine is an antimalarial drug that has been in use for over 40 years. Little is known of amodiaquine's mechanism of transport across membranes. Transport experiments of amodiaquine in Caco-2 cells showed a low recovery of 30% and rapid disappearance from the apical chamber. Compounds structurally similar to amodiaquine, and those affecting non-specific binding of amodiaquine or the pH of the system, were tested to unravel the mechanism behind these observations. Chloroquine and ammonium chloride increased the transmonolayer permeability of amodiaquine and decreased its accumulation in Caco-2 cells, whereas BSA had no effect. Chloroquine and BSA decreased plastic binding whereas ammonium chloride had no effect. This suggests that amodiaquine is trapped in acidic cell compartments such as lysosomes. Amodiaquine was also trapped in rat intestinal tissue. In addition, permeability from the apical to basolateral direction was significantly higher, suggesting an active uptake over the apical membrane of the rat tissue. It can be concluded that amodiaquine is trapped in acidic cell compartments due to its base properties and recovery may be improved by the use of ammonium chloride rather than BSA in transport experiments. Further studies are required to confirm whether amodiaquine is actively absorbed in the intestine. Copyright (C) 2008 John Wiley & Sons, Ltd.