低浓度聚氧乙烯蓖麻油对p-gp底物罗丹明123经肠黏膜透过性的影响

Effect of cremophor EL at low concentration on the permeabilities of rhodamine 123,a p-gp substrate across the rat intestinal membranes in vitro

目的观察低浓度聚氧乙烯蓖麻油对肠黏膜p-gp的调控作用。方法使用体外扩散池法评价罗丹明123(R123)经空肠、回肠和结肠黏膜的经时经吸收方向和分泌方向的透过量和透过系数(Papp),并测定不同浓度表面活性剂对R123和荧光素钠(CF)经肠黏膜透过性的影响。R123和CF在接受室中的浓度用荧光分光光度法测定。结果R123经肠道黏膜的透过性存在部位差,空肠、回肠和结肠的次序透过性依次减少;R123经肠道分泌方向的透过性显著高于其吸收方向的透过性。低浓度的聚氧乙烯蓖麻油具有增加R123经吸收方向的透过性,减少经分泌方向的透过性。但试验浓度的表面活性剂对CF的肠道转运没有影响。结论低浓度的聚氧乙烯蓖麻油可通过对p-gp功能的抑制而用于改善受p-gp介导药物的吸收,有望提高此类药物的口服生物利用度。

Objective to investigate the modulation of cremophor EL on the permeability characteristics of rhodamine123 （R123） across the different intestinal membranes. Methods The permeability （Papp） of R123 or fluorescein sodium （CF） via rat intestinal membranes at concentration of 5 μg · mL^-1 was evaluated by an in vitro diffusion chamber system after the membranes were isolated from the intestine in rat, with or without the co-administration of cremophor EL at different low concentrations. And the concentration of R123 or CF in the receptor was determined by the fluorospectrophotometry. Results There existed regional difference for the permeability of R123 across the rat intestinal membranes, which showed the permeabilities of R123 was gradually decreased from jejunum, then ileum to colon. On the other hand, the serosal-to-mucosal transport （S-M） of R123 was much greater than its mucosal-to-serosal （M-S） transport. With coadministration of eremophor EL at low concentrations, the absorptive directed transport of R123 was significantly increased while its secretory directed transport was decreased, and the concentration- dependent effect was also found. However, no action of cremophor EL at the test concentration was found for the transport of CF across the intestinal membranes. Conclusion It might be possible to improve the absorption of p-gp mediated drugs by coadministration of cremophor EL at low concentration, therefore to improve the oral bioavailability of these drugs.