Physiological mechanism for enhancement of paracellular drug transport
Physiological mechanism for enhancement of paracellular drug transport
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DOI：
10.1016/s0168-3659(99)00031-0
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发表时间：
1999-11-01
影响因子：
10.8
通讯作者：
Awazu, S
中科院分区：
文献类型：
--
作者：
Hayashi, M;Sakai, T;Awazu, S
我们研究了改善细胞旁药物转运的增强剂的作用机制。对于癸酸钠（C10），细胞内钙水平的增加被认为诱导钙调蛋白依赖性肌动蛋白丝的收缩，随后是细胞旁通路的扩张。尽管癸酰肉碱 (DC) 也增加细胞内钙水平，但其作用与钙调蛋白无关，因此，酰基肉碱的作用机制被认为与 C10 不同。其他酰基肉碱、月桂酰肉碱 (LC) 和棕榈酰肉碱 (PC) 以及有机酸、酒石酸 (TA) 和柠檬酸 (CA) 降低细胞内 ATP 水平和细胞内 pH 值。根据这些结果，认为酰基肉碱和有机酸的作用机制之一是细胞内酸中毒通过ATP水平的降低而增加钙水平，随后打开紧密连接。通过电解质的转运功能评估上述机制预期的膜功能障碍。 C10、LC 和 PC 增加的膜电导在 3 至 6 小时恢复期内恢复到控制值。另一方面，从短路电流（I-sc）获得的Cl-离子分泌被这些增强剂减少，但被C10标准化，但未被LC和PC标准化。因此，C10 可以被认为是比酰基肉碱更安全的增强剂。 (C) 1999 Elsevier Science B.V. 保留所有权利。
We examined the action mechanisms of enhancers that improve paracellular drug transport. For sodium caprate (C10), the increase in the intracellular calcium level was considered to induce the contraction of calmodulin-dependent actin filaments, followed by dilation of the paracellular pathway. Although decanoylcarnitine (DC) also increased the intracellular calcium level, the action was independent of calmodulin and thus, the action mechanism of acylcarnitines was considered to differ from that of C10. Other acylcarnitines, lauroylcarnitine (LC) and palmitoylcarnitine (PC) and organic acids, tartaric acid (TA) and citric acid (CA) decreased the intracellular ATP level and the intracellular pH. From these results, it was considered that one of the action mechanism of acylcarnitines and organic acids is that the intracellular acidosis increases the calcium level through the decrease in ATP levels, followed by opening the tight junction. Membrane dysfunction which was expected from the above mechanism was assessed by the transport function of electrolytes. Membrane conductance, which was increased by C10, LC and PC, returned to the control value during a 3- to 6-h recovery period. On the other hand, Cl- ion secretion, which was obtained from short-circuit current (I-sc), was decreased by these enhancers, but was normalized by C10 but not by LC and PC. Accordingly, C10 can be considered a safer enhancer than acylcarnitines. (C) 1999 Elsevier Science B.V. All rights reserved.