Improvement of intestinal drug absorption based on structural changes of tight junction and functional changes of P-glycoprotein

基于紧密连接结构变化和P-糖蛋白功能变化改善肠道药物吸收

• 批准号: 15590140
• 负责人: HAYASHI Masahiro
• 金额: $ 2.43万
• 依托单位: Tokyo University of Pharmacy and Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590140/
• 关键词: Tight Junction; P-glycoprotein; Absorption Enhancement; Peripheral Lymphocyte; Infective diseases; Ischemia; reperfusion; Inflammation Bowel Diseases; Gene Diagnosis; P-glycoprotein; 末梢リンパ球; 小腸虚血再灌流; 免疫抑制剤; 吸収部位差; トランスポーター; mdr1a mRNAレベル

We investigated the action mechanisms of absorption enhancers that improve paracellular and transcellular drug transport. Tartaric acid (TA) decreased the intracellular ATP level and the intracellular pH at the lower pH. From this results, it was considered that one of the action mechanism of TA is that the intracellular acidosis increases the calcium level through decrease in ATP levels, followed by opening the tight junction (TJ). TA and Pirotiodecan (PTD) also increased the transcellular transport based on the functional changes of P-glycoprotein (P-gp) in addition to TJ opening at the physiological pH. In particular, TA increased the absorption of rhodamine123 (Rho123) and daunorubicin in the ileum without TJ opening and change of expression level of P-gp. On the other hand, TA significantly inhibited the excretion of Rho123 from blood to lumen. These results suggest that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without cha … More nge the expression level of P-gp in the rat intestine. PTD had enhancing effects on nasal and intestinal absorption of Rho123 based on functional changes of P-gp. Consequently, we showed the expansion of TJ and inhibition of P-gp increase intestinal absorption of hydrophilic compounds and P-gp substrates.The multidrug resistance (mdr) gene codes for P-gp expressed on the surface of lymphocytes and intestinal epithelial cells. We measured peripheral lymphocyte (PBL) and mdr in infective diseases condition induced by lypopolysaccharide, ischemia/reperfusion (I/R), inflammation bowel diseases (IBD) and normal condition, to assess the relationship among PBL, mucosal intraepithelial lymphocyte (IEL) and mucosal epithelial cells (EC) mdr expression. Compared with controls, PBL mdr was significantly decreased in the diseases condition such as I/R and IBD. Both PBL and mucosal mdr expression appeared dependent of diseases activity, and there was a significant correlation both between PBL mdr expression and P-gp substrate absorption from intestine, and between IEL expression and EC expression. PBL and mucosal mdr expression may possibly play an important role in determination of the response of various diseases to P-gp substrate in the case such as glucocorticiod therapy. Less

我们研究了改善细胞细胞和跨细胞药物运输的苦难增强子的作用机制。 tart酸（TA）降低了细胞内ATP水平和下pH下的细胞内pH值。从此结果，可以认为TA的作用机理之一是细胞内酸中毒通过ATP水平降低而增加钙水平，然后打开紧密连接（TJ）。除了在物理pH下的TJ开放外，TA和Pirotiodecan（PTD）还基于P-糖蛋白（P-GP）的功能变化增加了跨细胞转运。特别是，ta在回肠中增加了若丹明123（Rho123）和daunorubicin的丰度，而无需TJ开放和P-gp表达水平的变化。另一方面，TA显着抑制了Rho123从血液到流明的排泄。这些结果表明，TA增加了P-gp底物的肠道丰度，可以通过抑制没有CHA的P-gp功能……更多的是大鼠肠中P-gp的表达水平。基于P-gp的功能变化，PTD对RHO123的鼻和肠道丧失具有增强的影响。因此，我们显示了TJ的膨胀和P-gp的抑制增加了亲水性化合物和P-gp底物的肠道丧失。在淋巴细胞和肠上皮细胞表面表达的P-gp的多次抗药性（MDR）基因代码。我们测量了叶型糖化，缺血/再灌注（I/R），炎症肠疾病（IBD）和正常状态引起的外周淋巴细胞（PBL）和MDR感染性疾病状况，以评估PBL，粘膜内层淋巴细胞的粘膜之间的关系。与对照组相比，在I/R和IBD等疾病状态下，PBL MDR显着降低。 PBL和粘膜MDR表达似乎都取决于疾病活性，并且PBL MDR表达与P-GP底物在肠道以及IEL表达和EC表达之间存在显着相关性。在确定各种疾病对P-gp底物的反应中，PBL和粘膜MDR表达在诸如葡萄糖皮层治疗的情况下可能起重要作用。较少的

项目成果

Ischemia/reperfusion injury in the monolayers of human intestinal epithelial cell line Caco 一 2 cell and its recovery by antioxidant

人肠上皮细胞系Caco 2细胞单层缺血/再灌注损伤及其抗氧化修复

• 期刊: (in Press)
• 作者: 富田 幹雄;林 正弘;Hiroshi Otake et al.;Aiko Iida et al.;Mikio Tomita et al.;Mikio Tomita et al.;Hayashi Iizasa et al.;Rie Ohkubo et al.;Mikio Tomita;Hisashi Iizasa et al.;Rie Ohkubo et al.;Nobuaki Eto et al.;Mayuko Nagira et al.
• 通讯作者: Mayuko Nagira et al.

Tight JunctionおよびP-糖タンパク質の機能修飾に基づいた薬物吸収改善

基于紧密连接和 P-糖蛋白功能修饰改善药物吸收

• 发表时间: 2005
• 期刊: Drug Delivery System 20(4)
• 作者: 富田 幹雄;林 正弘
• 通讯作者: 林 正弘

Comparative study of flux of FITC-labeled Dextran 4000 on normal (iso)- and hyper-osmolarity in basal side in caco-2 cell monolayers.

• DOI: 10.2133/dmpk.18.404
• 发表时间: 2003-01-01
• 期刊: Drug metabolism and pharmacokinetics
• 影响因子: 2.1
• 作者: Ohkubo, Rie;Tomita, Mikio;Hayashi, Masahiro
• 通讯作者: Hayashi, Masahiro

Transporter-mediated drug interactions during intestinal absorption

肠道吸收过程中转运蛋白介导的药物相互作用

• 发表时间: 2003
• 期刊: Organ Biology 10(4)
• 作者: 富田 幹雄;林 正弘;Hiroshi Otake et al.;Aiko Iida et al.;Mikio Tomita et al.;Mikio Tomita et al.;Hayashi Iizasa et al.;Rie Ohkubo et al.;Mikio Tomita
• 通讯作者: Mikio Tomita

Effectiveness of Pirotiodecane, absorption enhancer, on nasal absorption in rabbits.

吡罗碘烷（吸收促进剂）对兔子鼻腔吸收的有效性。

• 发表时间: 2005
• 期刊: Drug Metab.and Pharmacokinet. 20(1)
• 作者: 富田幹雄;林正弘;Toshinobu Seki et al.;Hiroshi Otake et al.
• 通讯作者: Hiroshi Otake et al.