| Co-Investigator(Kenkyū-buntansha) |
KIMURA Toshikiro Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (10025710)
OGAWARA Ken-ichi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Research Assistant, 大学院・医歯薬学総合研究科, 助手 (30291470)
|
|---|
| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
|
|---|
| Research Abstract |
In the small intestine, there are autonomic nerves, the enteric nerve system (ENS), which is independent of the central nervous system (CNS). It is well know that ENS 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 drug absorption and secretion via some specialized mechanisms. First of all, the effect of ENS on PepT1, which is well known to mediate the absorption of β-lactam antibiotics, was investigated by employing cephalexin (CEX), as a model compound. Using a rat isolated intestinal sheet only with submucosal plexus, the transport of CEX was enhanced by the stimulation of adrenergic neurons with epinephrine or clonidine, suggesting that α_2 receptor
… More
could be involved in the enhancement of PepT1 activity. Furthermore, the enhancement of translocation of PepT1 to brush border membrane would be partly responsible for the enhanced activity of PepT1. Second, the effect of ENS on P-glycoprotein (P-gp), an efflux pump for mainly lipophilic organic cations, was investigated by employing rhodamine 123, a typical substrate for P-gp, as a model compound. Three different methods such as the vascular-luminal perfusion study, the transport study with the isolated intestinal sheet and Caco-2 cells were employed, but the stimulation of adrenergic neuron by epinephrine attenuated P-gp activity. Western blot analysis showed that the expression level of P-gp in brush border membrane tended to decrease, suggesting that the decrease in the expression level could be partly responsible for the decrease in P-gp activity under the stimulation of adrenergic neuron. Furthermore, clonidine, a selective α_2 agonist, tended to decrease, and dobutamine, a selective β_1 agonist, tended to increase the activity of P-gp. Dibutyryl cAMP significantly enhanced P-gp activity. These results that α_2 and β_2 receptors could be involved in the regulation of P-gp activity and that cytosolic cAMP play an important role in P-gp activity. Less
|
