Higaki Kazutaka, Sone Miki, Ogawara Ken-ichi, Kimura Toshikiro
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Drug Metab Pharmacokinet. 2004 Jun;19(3):198-205. doi: 10.2133/dmpk.19.198.
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.
为研究肠神经系统（ENS）对小肠药物吸收的调节作用，以酚红作为吸收较差的模型化合物，进行了血管-肠腔灌注研究和体外转运研究。在血管-肠腔灌注大鼠小肠制备中，通过向血管灌注液中添加肾上腺素（一种肾上腺素能激动剂）或氨甲酰甲胆碱（一种胆碱能激动剂），研究ENS对酚红肠道吸收的影响。通过血管灌注液的回收、净水流以及安替比林（一种吸收良好的药物）的吸收能力来检查灌注肠的活力，结果证实灌注小肠制剂的功能至少维持1小时。肾上腺素或氨甲酰甲胆碱对小肠功能的影响分别表现为净水吸收增加或促进水分泌。这些现象是在刺激肾上腺素能或胆碱能神经元时通常会观察到的。然后，我们在血管-肠腔灌注制剂中研究了酚红的小肠吸收情况。酚红的吸收清除率（CL(abs)）在灌注1小时期间逐渐增加，但用含肾上腺素的灌注液进行20分钟的血管灌注使酚红的CL(abs)保持恒定且显著低于对照研究。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会导致酚红小肠吸收减少。另一方面，与对照研究相比，氨甲酰甲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甲胆碱后，酚红的CL(abs)再次降低。使用分离的空肠片进行的体外转运研究也表明，浆膜溶液中的肾上腺素显著降低了酚红的转运，这可归因于肾上腺素作用导致跨膜电阻（TER）增加，从而使细胞旁途径收紧。另一方面，尽管氨甲酰甲胆碱对酚红转运和TER的影响在统计学上不显著，但酚红的转运倾向于增加，且TER值小于对照研究。
