Regulation of drug absorption and secretion from gastrointestinal via specialized mechanisms by enteric nervous system

在小肠中，有自主神经，即独立于中枢神经系统的肠神经系统（ENS）。众所周知，ENS调节小肠的运动以及小肠中水和/或电解质的运输。然而，关于ENS对药物从小肠吸收的影响的信息很少。我们一直在继续系统地研究ENS在小肠药物吸收中的作用。在这个项目中，我们主要研究ENS通过一些特殊的机制对药物吸收和分泌的影响。首先，以头孢氨苄（CEX）为模型化合物，研究ENS对介导β-内酰胺类抗生素吸收的PepT1的影响。在仅粘膜下神经丛的大鼠离体肠片上，肾上腺素或可乐定刺激肾上腺素能神经元可促进CEX的转运，提示α_2受体可能参与了PepT1活性的增强。此外，PepT1向刷状膜的易位增强可能是PepT1活性增强的部分原因。其次，以p -糖蛋白的典型底物罗丹明123为模型化合物，研究了ENS对p -糖蛋白（P-gp）的影响。p -糖蛋白主要是亲脂性有机阳离子的外排泵。采用血管-管腔灌注法、离体肠片转运法和Caco-2细胞法三种不同的方法，但肾上腺素刺激肾上腺素能神经元可使P-gp活性减弱。Western blot分析显示，P-gp在刷状缘膜的表达水平有降低的趋势，提示在肾上腺素能神经元的刺激下，P-gp表达水平的降低可能是其活性降低的部分原因。α_2选择性激动剂可乐定有降低P-gp活性的趋势，β_1选择性激动剂多巴酚丁胺有提高P-gp活性的趋势。二丁基cAMP显著增强P-gp活性。结果表明α_2和β_2受体参与了P-gp活性的调控，胞内cAMP在P-gp活性的调控中起重要作用。少

In the small intestine, there are autonomic nerves, the enteric nerve system (ENS), which is independent of the central nervous system (CNS). It is well know that ENS regulates the movement of small intestine and the transport of water and/or electrolytes in the small intestine. However, there is little information about the effect of ENS on drug absorption from the small intestine. We have been continuing systematically to investigate the role of ENS in drug absorption from the small intestine. In this project, we focused on the effect of ENS on drug absorption and secretion via some specialized mechanisms. First of all, the effect of ENS on PepT1, which is well known to mediate the absorption of β-lactam antibiotics, was investigated by employing cephalexin (CEX), as a model compound. Using a rat isolated intestinal sheet only with submucosal plexus, the transport of CEX was enhanced by the stimulation of adrenergic neurons with epinephrine or clonidine, suggesting that α_2 receptor … More could be involved in the enhancement of PepT1 activity. Furthermore, the enhancement of translocation of PepT1 to brush border membrane would be partly responsible for the enhanced activity of PepT1. Second, the effect of ENS on P-glycoprotein (P-gp), an efflux pump for mainly lipophilic organic cations, was investigated by employing rhodamine 123, a typical substrate for P-gp, as a model compound. Three different methods such as the vascular-luminal perfusion study, the transport study with the isolated intestinal sheet and Caco-2 cells were employed, but the stimulation of adrenergic neuron by epinephrine attenuated P-gp activity. Western blot analysis showed that the expression level of P-gp in brush border membrane tended to decrease, suggesting that the decrease in the expression level could be partly responsible for the decrease in P-gp activity under the stimulation of adrenergic neuron. Furthermore, clonidine, a selective α_2 agonist, tended to decrease, and dobutamine, a selective β_1 agonist, tended to increase the activity of P-gp. Dibutyryl cAMP significantly enhanced P-gp activity. These results that α_2 and β_2 receptors could be involved in the regulation of P-gp activity and that cytosolic cAMP play an important role in P-gp activity. Less