Regulation of drug absorption from small intestine by enteric nervous system I: a poorly absorbable drug via passive diffusion.
Regulation of drug absorption from small intestine by enteric nervous system I: a poorly absorbable drug via passive diffusion.
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DOI：
10.2133/dmpk.19.198
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发表时间：
2004-06-01
影响因子：
2.1
通讯作者：
Kimura, Toshikiro
中科院分区：
文献类型：
--
作者：
Higaki, Kazutaka;Sone, Miki;Kimura, Toshikiro
为探讨肠神经系统对药物小肠吸收的调节作用，采用酚红作为吸收不良模型化合物，进行了血管-管腔灌注研究和体外转运研究。在大鼠小肠血管灌流模型上，分别向灌流液中加入肾上腺素（肾上腺素能激动剂）和胆碱能激动剂氨甲酰胆碱（胆碱能激动剂），观察ENS对酚红在小肠吸收的影响。通过血管灌流液的恢复、净水通量和安替比林（一种吸收良好的药物）的吸收性来检查灌流肠的活力，并且证实灌流小肠制剂的功能至少维持1小时。肾上腺素或氨甲酰胆碱对小肠功能的影响被认为是净水吸收的增加，或促进水分分泌。这些现象是肾上腺素能或胆碱能神经元受到刺激时通常观察到的现象。然后，我们研究了酚红在血管腔灌流制剂中的小肠吸收。灌流1h时，酚红的吸收清除率（CL（abs））逐渐增加，但用含肾上腺素的灌流液灌流20 min时，使酚红的CL（abs）保持不变，并显著低于对照组。此外，在用不含任何激动剂的灌注液更换灌注液后，酚红的CL（abs）再次开始增加。这些结果清楚地表明，肾上腺素刺激肾上腺素能神经元导致酚红的小肠吸收减少。另一方面，与对照研究相比，氨甲酰胆碱的血管灌注导致酚红的CL（abs）增加。从血管灌注液中去除氨甲酰胆碱再次降低了酚红的CL（abs）。使用离体空肠片的体外转运研究也表明，serenine溶液中的肾上腺素显著降低了酚红的转运，这可以归因于肾上腺素的作用使跨粘膜电阻（TER）增加，从而收紧了细胞旁途径。另一方面，尽管氨甲酰甲胆碱对酚红的转运和TER的影响在统计学上不显著，但酚红的转运有增加的趋势，并且TER的值小于对照研究的值。
To investigate the regulation of drug absorption from the small intestine by the enteric nervous system (ENS), the vascular-luminal perfusion study and the in-vitro transport study were performed by employing phenol red as a poorly absorbable model compound. The effect of ENS on the intestinal absorption of phenol red was examined by adding epinephrine, an adrenergic agonist, or bethanechol, a cholinergic agonist into the vascular perfusate in the vascular-luminal perfused rat small-intestine preparation. The viability of the perfused intestine was checked by the recovery of the vascular perfusate, net water flux and absorbability of antipyrine, a well absorbable drug, and it was confirmed that the function of the perfused small-intestine preparation was maintained for at least 1 hr. The effect of epinephrine or bethanechol on the function of the small intestine was recognized as the increase in net water absorption, or the promotion of the water secretion, respectively. These phenomena are ones that are typically observed when adrenergic or cholinergic neuron is stimulated. Then, we investigated the small-intestinal absorption of phenol red in the vascular-luminal perfused preparation. Absorption clearance (CL(abs)) of phenol red was gradually increasing during the perfusion for 1 hr, but the 20-min vascular perfusion with the perfusate containing epinephrine made CL(abs) of phenol red constant and significantly lower than those for control study. Furthermore, after the perfusate was changed with the one without any agonist, again, CL(abs) of phenol red started to increase. These results clearly indicate that the stimulation of adrenergic neuron by epinephrine leads to the decrease in the small-intestinal absorption of phenol red. On the other hand, the vascular perfusion of bethanechol resulted in the increase in CL(abs) of phenol red comparing to the control study. Removing bethanechol from the vascular perfusate decreased CL(abs) of phenol red, again. The in-vitro transport study using the isolated jejunum sheet also showed that epinephrine in the serosal solution significantly decreased the transport of phenol red, which can be ascribed to the paracellular pathway tightened by the action of epinephrine because of the increase in transmucosal electrical resistance (TER). On the other hand, although the effect of bethanechol on both the transport of phenol red and TER was not statistically significant, the transport of phenol red tended to increase and the values of TER are smaller than those of control study.