Effect of neurohumoral control on gastrointestinal absorption of drugs

本研究以苯酚红（PR）为模型化合物，探讨了肠道神经系统（ENS）通过被动扩散机制对药物吸收的影响。通过大鼠小肠血管和腔内灌注实验和体外平行扩散室转运实验来评价肾上腺素和亚麻酚对ENS的调节作用。肾上腺素的输注增加了水分的吸收。相反，肾上腺素能显著降低PR的吸收，并且在血管灌注液中去除肾上腺素后，这种作用消失，说明肾上腺素的作用应该是可逆的。在大鼠空肠扩散室实验中，肾上腺素能迅速降低初始PD和Isc，这可能归因于氯离子吸收的增强。随着肾上腺素的加入，Rm和PR的吸收率分别增加和减少。这些结果提示肾上腺素能神经可能通过调节紧密连接来调节药物的被动转运，而不是通过溶剂阻力来调节。在药物输注和恢复期间，血管灌注液中加入麻酚可使净水通量转化为分泌量，在开始输注麻酚时，PR的吸收率略有下降，随后PR的吸收率增加。从这些结果中发现，ENS不仅可以调节血流、肠蠕动、水和/或电解质的运输，还可以调节药物在肠道中的吸收。

In the present study, we tried to investigate the effect of enteric nervous system (ENS) on the drug absorption via passive diffusion mechanism, using phenol red (PR) as a poorly absorbable model compound. To modulate ENS, epinephrine and bethanechol were employed, and their effects were evaluated by the vascular and luminal perfusion study in rat small intestine and the in vitro transport study using the side-by-side diffusion chamber.The infusion of epinephrine increased water absorption. On the contrary, the absorption of PR was significantly reduced by epinephrine and this effect of epinephrine disappeared by removing epinephrine from the vascular perfusate, indicating that the effects of epinephrine should be reversible, In the diffusion chamber experiments using rat jejunum, epinephrine rapidly reduced initial PD and Isc, which would be ascribed to the enhancement of chloride absorption. Rm and the absorption of PR increased and reduced with the addition of epinephrine, respectively. These results suggest that adrenergic nerves might regulate the passive transport of drugs by modulating tight junction, but not by solvent drag.The addition of bethanechol into vascular perfusate converted net water flux to secretion during both the drug infusion and recovery periods, At the beginning of bethanechol infusion, the absorption rate of PR slightly decreased, and then PR absorption increased. Removing bethanechol from the vascular perfusate rapidly reduced the absorption of PR.From these results, it was found that ENS should regulate not only the blood flow, the intestinal motility and the transport of water and/or electrolytes but also the absorption of drug in the intestine.