Regulation of drug absorption from gastrointestinal tract by enteric nerve system

在小肠中，存在自主神经，肠神经系统（ENS），其独立于中枢神经系统（CNS）。ENS由胆碱能神经元、肾上腺素能神经元和非肾上腺素能神经元组成，是一个独立的整合系统，具有与CNS相似的结构和功能。ENS对小肠功能的影响已在平滑肌的调节和水和/或电解质的转运方面进行了深入研究。然而，关于其对小肠药物吸收的影响的信息很少。我们继续研究ENS在药物从小肠吸收中的作用，并且已经表明，刺激肾上腺素能神经元引起通过被动扩散的药物吸收的抑制，并且刺激胆碱能神经元引起其增强。在本项目中，我们研究了ENS对药物吸收的影响，通过一些专门的mec ...更多信息 汉民族首先，通过使用PEPT 1的典型底物头孢氨苄（CEX）作为模型化合物，研究ENS对寡肽转运蛋白PEPT 1的影响，所述寡肽转运蛋白PEPT 1众所周知介导β-内酰胺抗生素的吸收。在原位闭环研究中，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。用Caco-2细胞进行的转运研究也表明，肾上腺素或可乐定增强CEX转运。由于PEPT 1的典型底物甘氨酰肌氨酸（glycylsarcosine）可抵消它们的增强作用，而CEX的被动扩散转运减少，这些神经递质可能通过α_2受体激活肽转运体的活性。α_1-、β_1-、β_2-、-受体激动剂和氨甲酰胆碱均能增加CEX的被动扩散转运，这可能与TEER降低有关。第二，5-羟色胺（5-HT），一种神经递质的多巴胺能神经元，对P-糖蛋白（P-gp），亲脂性有机阳离子的外排泵的耗竭的影响，采用奎尼丁，一个典型的底物P-gp，作为模型化合物进行了研究。小肠中5-HT的消耗导致奎尼丁转运的增强，这是通过跨细胞途径，并通过一种可被维拉帕米（P-gp的典型底物）抑制的机制。提示5-HT耗竭后P-gp活性增强。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