Regulation of drug absorption from gastrointestinal tract by enteric nerve system

2001 Fiscal Year Final Research Report Summary

• Project/Area Number: 12672215
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 応用薬理学・医療系薬学
• Research Institution: OKAYAMA UNIVERSITY
• Principal Investigator: HIGAKI Kazutaka Okayama University, Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60284080)
• Co-Investigator(Kenkyū-buntansha): OGAWARA Ken-ichi Okayama University, Graduate school of Natural Science and Technology, Research Assistant, 大学院・自然科学研究科, 助手 (30291470) ; KIMURA Toshikiro Okayama University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (10025710)
• Project Period (FY): 2000 – 2001
• Keywords: enteric nerve system / gastrointestinal absorption / oligopeptide transporter / absorption enhancement / cephalexin / P-glycoproteir / 5-HT / quinidine

Research Abstract

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 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.