Regulation of drug absorption from gastrointestinal tract by enteric nerve system

在小肠中，有自主神经，肠神经系统(ENS)，它独立于中枢神经系统(CNS)。ENS由胆碱能、肾上腺素能和非肾上腺素能非软骨能神经元组成，是一个独立的整合系统，具有与中枢神经系统相似的结构和功能特性。ENS对小肠功能的影响已被广泛研究，主要是通过调节小肠平滑肌和水或电解质的运输来实现的。然而，关于它对药物从小肠吸收的影响的信息很少。我们继续研究ENS在小肠药物吸收中的作用，并已证明刺激肾上腺素能神经元通过被动扩散抑制药物吸收，刺激胆碱能神经元导致药物吸收增强。在这个项目中，我们通过一些特殊的mec…来研究ens对药物吸收的影响。更多的韩语。首先，以β-内酰胺类抗生素的典型底物头孢氨苄为模型化合物，研究了ENS对寡肽转运体PEPT1的影响。用肾上腺素或可乐定刺激肾上腺素能神经元，可增强CEX的转运。Caco-2细胞的转运研究也表明，肾上腺素或可乐定可促进CEX的转运。由于PEPT1的典型底物甘氨酰肌氨酸抵消了它们的增强作用，而且CEX通过被动扩散的转运被认为减少，这些神经递质可能通过α_2受体刺激多肽转运体的活性。α_1~-、β_1~-、β_2~-、激动剂和苯基儿茶酚可通过被动扩散增加CEX的转运，这可能是TEER降低的部分原因。其次，以5-羟色胺的典型底物奎尼丁为模型化合物，研究了5-羟色胺能神经递质5-羟色胺(5-HT)的耗竭对P-糖蛋白(P-gp)的影响。5-羟色胺在小肠中的耗竭导致奎尼丁转运的增强，这是通过跨细胞途径实现的，其机制可被P-gp的典型底物维拉帕米所抑制。这些结果表明，5-羟色胺的缺乏可增强P-gp的活性。较少

In the small intestine, there are autonomic nerves, the enteric nerve system (ENS), which is independent of the central nervous system (CNS). ENS, composed of cholinergic, adrenergic and nonadrenergic nonchoninergic neurons, is recognized as an independent integrative system with structural and functional properties similar to those of CNS. The effect of ENS on the small intestinal functions has been intensively studied in terms of the regulation of the smooth muscle and the transport of water and/or electrolytes. However, there is little information about its effect on drug absorption from the small intestine. We continue to investigate the role of ENS in drug absorption from the small intestine and have already shown that the stimulation of adrenergic neuron caused the suppression of drug absorption via passive diffusion and that the stimulation of cholinergic neuron caused its enhancement. In this project, we investigated the effect of ENS on drug absorption via some specialized mec … More hanisms. First of all, the effect of ENS on the oligopeptide transporter PEPT1, which is well known to mediate the absorption of β-lactam antibiotics, was investigated by employing cephalexin (CEX), a typical substrate for PEPT1, as a model compound. The transport of CEX was enhanced by the stimulation of adrenergic neurons with epinephrine or clonidine in the in situ closed loop study. The transport study with Caco-2 cells also showed that epinephrine or clonidine enhanced CEX transport. As glycylsarcosine, a typical substrate for PEPT1, canceled out their enhancing effect and as the transport of CEX via passive diffusion was suggested to decrease, these neurotransmitters would stimulate the activity of peptide transporter probably via α_2-receptor. α_1-, β_1-, β_2-, -agonists and bethanechol tended to increase the transport of CEX via passive diffusion, which might be partly explained by the decreases in TEER. Second, the effect of the depletion of serotonin (5-HT), a neurotransmitter for serotonergic neuron, on P-glycoprotein (P-gp), an efflux pump for lipophilic organic cations, was investigated by employing quinidine, a typical substrate for P-gp, as a model compound. Depletion of 5-HT in the small intestine resulted in the enhancement of quinidine transport, which was via transcellular route and via a mechanism which can be inhibited by verapamil, a typical substrate for P-gp. These results suggested that the activity of P-gp was enhanced under the depletion of 5-HT. Less