Iida Aiko, Tomita Mikio, Hayashi Masahiro
Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Drug Metab Pharmacokinet. 2005 Apr;20(2):100-6. doi: 10.2133/dmpk.20.100.
It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum.
据报道，抑制P-糖蛋白（P-gp）可使P-gp底物在肠道的吸收得到改善。事实上，在体外实验中抑制P-gp后，观察到P-gp底物跨肠上皮细胞的通透性增加。为了开发含有P-gp抑制剂和P-gp底物的制剂以供实际使用，有必要了解体外实验获得的结果在全身水平上是否可重现。找出肠道中P-gp活性的区域差异也很重要。在本研究中，我们使用原位肠袢法研究了P-gp的特异性抑制剂维拉帕米是否能改善P-gp底物罗丹明123（Rho123）从大鼠空肠、回肠和结肠的吸收。实验过程中肠袢中的水分含量下降，导致肠袢中Rho123浓度发生显著变化。因此，为了准确测定Rho123的吸收率，有必要测量水分移动情况。结果发现水分移动存在区域差异，即结肠中最大，其次是回肠。维拉帕米在任何肠道区域均未改变水分移动情况。当通过水分移动校正肠袢中Rho123的浓度时，Rho123的清除率顺序为空肠（1.15微升/分钟/厘米）、结肠（0.83微升/分钟/厘米）和回肠（0.47微升/分钟/厘米）。在维拉帕米存在的情况下，空肠和回肠的Rho123清除率显著增加，但结肠中未增加（回肠：2.08微升/分钟/厘米，结肠：1.14微升/分钟/厘米，空肠：1.28微升/分钟/厘米）。这些结果表明，P-gp抑制空肠和回肠中的药物吸收。根据这些结果，可以在原位实验中评估P-gp的作用及其区域差异。特别是，抑制P-gp会导致P-gp底物的吸收增加，且仅限于空肠和回肠。
