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

我们研究了吸收促进剂改善药物的细胞旁转运和跨细胞转运的作用机制。酒石酸（TA）降低细胞内ATP水平，降低细胞内pH值，其作用机制之一是细胞内酸中毒通过降低ATP水平，增加细胞内钙离子浓度，进而开放细胞间紧密连接（TJ）。TA和Pirotiodecan（PTD）也增加了跨细胞转运的基础上的功能变化的P-糖蛋白（P-gp）除了TJ开放在生理pH值。特别是，TA增加了罗丹明123（Rho 123）和柔红霉素在回肠的吸收没有TJ开放和P-gp的表达水平的变化。另一方面，TA显着抑制Rho 123从血液到管腔的排泄。这些结果表明，TA增加了P-gp底物的肠吸收，可能是通过抑制P-gp功能而不改变P-gp底物的活性。 ...更多信息 检测大鼠小肠P-gp的表达水平。PTD对Rho 123的鼻黏膜和小肠吸收有促进作用，其机制可能与P-gp功能改变有关。因此，我们发现TJ的扩增和P-gp的抑制增加了肠对亲水性化合物和P-gp底物的吸收，多药耐药（multidrug resistance，mdr）基因编码表达于淋巴细胞和肠上皮细胞表面的P-gp。通过检测脂多糖诱导的感染性疾病、缺血再灌注（I/R）、炎症性肠病（IBD）及正常人外周血淋巴细胞（PBL）及多药耐药基因（mdr）的表达，探讨PBL、黏膜上皮内淋巴细胞（IEL）及黏膜上皮细胞（EC）mdr表达的关系。与对照组相比，I/R和IBD等疾病状态下PBL mdr显著降低。PBL和粘膜mdr表达均与疾病活动有关，PBL mdr表达与肠P-gp底物吸收有关，IEL表达与EC表达有关。PBL和粘膜mdr表达可能在确定各种疾病对P-gp底物的反应中起重要作用，如糖皮质激素治疗。少

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