2007 Fiscal Year Final Research Report Summary
Regulation of drug absorption by enteric nervous system: Studies on drug secretion via specialized mechanisms.
| Project/Area Number |
18590142
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Okayama University |
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Principal Investigator |
HIGAKI Kazutaka Okayama University, Graduate School of Medicine. Dentistry and Pharmaceutical Sciences, Associate Professor (60284080)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Toshikiro Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor (10025710)
OGAWARA Ken-ichi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Assistant Professor (30291470)
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| Project Period (FY) |
2006 – 2007
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| Keywords | enteric nervous system / P-glycoprotein / adrenaline / clonidine / Western blot / brush border membrane / trafficking / rhodamine123 |
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| Research Abstract |
The enteric nervous system (ENS), independent of the central nervous system (CNS), regulates the movement of small intestine and the transport of water and/or electrolytes in the small intestine. However, there is little information about the effect of ENS on drug absorption from the small intestine. We have been continuing systematically to investigate the role of ENS in drug absorption from the small intestine. In this project, we focused on the effect of ENS on function of P-glycoprotein (P-gp), which is well known to pump out many important drugs. Employing rhodamine123, a typical substrate for P-gp, as a model compound, the effect of addition of adrenaline on P-gp function was investigated with three different methods such as the vascular-luminal perfusion study, the transport study with the isolated intestinal sheet and Caco-2 cells. As a result, the stimulation of adrenergic neuron by adrenaline attenuated P-gp activity in all the three methods. Western blot analysis showed that
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the expression level of P-gp in brush border membrane (BBM) decreased, which was significantly correlated with the decrease in P-gp activity, indicating that the decrease in the expression level in BBM could be partly responsible for the decrease in P-gp activity On the other hand, the whole expression level of P-gp in the epithelial cells was found not to be changed by the addition of adrenaline, suggesting that the trafficking rate of P-gp from intracellular pool to BBM was decreased by the addition of adrenaline. Since clonidine, a selective α_2 agonist, provided the results similar with adrenaline, as receptor could be involved in the regulation of P-gp activity. It was also found that adrenaline decreased the intracellular level of cAMP and that PICA inhibitor decreased P-gp activity Furthermore, dibutyryl cAMP significantly enhanced P-gp activity. Taken all together, adrenaline decreases P-gp activity by attenuating the expression level of P-gp on BBM, which could be mediated by the decrease in cyclic AMP level and subsequent decrease in PKA activity. Less
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[Journal Article] Regulation of drug absorption from small intestine by enteric nervous system : Studies on passive diffusion2007
Author(s)
T., Kimoto, M., Takanashi, M., Sasaki, K., Ogawara, T., Kimura, K., Higaki
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Journal Title
Drug Metab. Rev 39(1)
Pages: 94
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Regulation of P-glycoprotein function by enteric nervous system : Efflux activity and intracellular migration of P-glycoprotein in intestinal epithelial cells2007
Author(s)
H., Mukai, H., Hiraoka, K., Matsushita, K., Ogawara, T., Kimura, K., Higaki
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Journal Title
Drug Metab. Rev 39(1)
Pages: 274-275
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of Drug Absorption from Small Intestine by Enteric Nervous System : Studies on Passive Diffusion2007
Author(s)
Takahiro, Kimoto, Masashi, Takanashi, Moeko, Sasaki, Ken-ichi Ogawara, Toshikiro, Kimura, Kazutaka, Higaki
Organizer
8th International ISSX Meeting
Place of Presentation
Sendai International Center, Sendai, Japan
Year and Date
20071009-12
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of P-glycoprotein Function by Enteric Nervous System : Efflux Activity and Intracellular Migration of P-glycoprotein in Intestinal Epithelial Cells2007
Author(s)
Hironori, Mukai, Hideo, Hiraoka, Kotaro, Matsushita, Kenichi, Ogawara, Toshikiro, Kimura, Kazutaka, Higaki
Organizer
8th International ISSX Meeting
Place of Presentation
Sendai International Center, Sendai, Japan
Year and Date
20071009-12
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of drug absorption from small intestine by enteric nervous system : Studies on passive diffusion and P-gp function2007
Author(s)
Takahiro, Kimoto, Hideo, Hiraoka, Hironori, Mukai, Moeko, Sasaki, Kenichi, Ogawara, Toshikiro, Kimura, Kazutaka, Higaki
Organizer
4th Pharmaceutical Sciences World Congress
Place of Presentation
RAI Congress Center, Amsterdam, Netherlands
Year and Date
20070422-25
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of drug absorption via passive diffusion from small intestine by enteric nervous system2006
Author(s)
Takahiro, Kimoto, Moeko, Sasaki, Ken-ichi, Ogawara, Toshikiro, Kimura, Kazutaka, Higaki
Organizer
21st Japanese Society for the Study of Xenobiotics Annual Meeting
Place of Presentation
Tower Hall Funabori, Tokyo, Japan
Year and Date
20061129-1201
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Regulation of drug transport via P-glycoprotein by enteric nervous system in Caco-2 monolayers2006
Author(s)
Hironori, Mukai, Hideo, Hiraoka, Kotaro, Matsushita, Kenichi, Ogawara, Toshikiro,Kimura, Kazutaka, Higaki
Organizer
21st Japanese Society for the Study of Xenobiotics Annual Meeting
Place of Presentation
Tower Hall Funabori, Tokyo, Japan
Year and Date
20061129-1201
Description
「研究成果報告書概要(欧文)」より
