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细胞旁和跨细胞药物转运的作用机制。酒石酸(TA)在较低pH时降低细胞内ATP水平和细胞内pH。由此认为，TA的作用机制之一是细胞内酸化通过降低ATP水平，进而开放紧密连接(TJ)，从而增加细胞内钙离子水平。在生理pH条件下，除了TJ开放外，Ta和Pirotiodecan(PTD)还基于P-糖蛋白(P-gp)的功能变化而增加跨细胞转运。尤其是TA可增加罗丹明123(Rho123)和柔红霉素在回肠的吸收，而不影响TJ开放和P-gp的表达水平。另一方面，TA显著抑制Rho123从血液到管腔的排泄。这些结果表明，TA促进P-gp底物的肠道吸收，可能是通过抑制P-gp功能而不是CHA…进一步观察P-gp在大鼠肠道中的表达水平。PTD通过对P-gp功能的改变，促进Rho123在鼻腔和肠道的吸收。因此，我们发现TJ的扩张和P-gp的抑制增加了肠道对亲水性化合物和P-gp底物的吸收。P-gp的多药耐药(MDR)基因编码表达于淋巴细胞和肠上皮细胞表面。通过检测脂多糖感染性疾病、缺血再灌注(I/R)、炎症性肠病(IBD)和正常状态下外周血淋巴细胞(PBL)和多药耐药(MDR)的表达，探讨PBL与黏膜上皮内淋巴细胞(IEL)和粘膜上皮细胞(EC)MDR表达的关系。与对照组相比，PBL MDR在I/R、IBD等疾病状态下显著降低。PBL和粘膜MDR表达均与疾病活动性有关，PBL MDR表达与肠道P-gp底物吸收、IEL表达与EC表达均显著相关。PBL和粘膜MDR的表达可能在糖皮质激素治疗等多种疾病对P-gp底物的反应中起重要作用。较少

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