几种表面活性剂对p-gp底物罗丹明123经肠粘膜透过性的影响4.docVIP

几种表面活性剂对p-gp底物罗丹明123经肠粘膜透过性的影响 李国锋*，侯连兵，黄蓓蓓，任非，李青 （南方医科大学南方医院药学部，广州 510515） 摘要：目的 观察低浓度表面活性剂聚氧乙烯蓖麻油，Labrasol和吐温－80对肠粘膜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，回肠和结肠粘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）经肠粘膜透过性的影响。R123和CF在接受室中的浓度用荧光分光光度法测定。结果 R123经肠道粘膜的透过性存在部位差，即以空肠，回肠和结肠的次序透过性依次减少。另一方面，R123经肠道分泌方向的透过性显著地高于其吸收方向的透过性。低浓度的3种表面活性剂具有增加R123经吸收方向的透过性，减少经分泌方向的透过性，并存在浓度依赖性。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，Labrasol和吐温－80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，提高此类药物的口服生物利用度。P－糖蛋白,；Labrasol；吐温－80；扩散池fluorescein sodium (CF) via rat intestinal membranes at concentration of 5μg.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 the above three surfactants at different low concentrations. And the concentration of R123 or CF in the receptor was determined by the fluorospectrophotometry. RESULTS There exists regional difference for the permeability of R123 across the rat intestinal membranes, which means 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 co-administration of the 3 surfactants 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 the 3 surfactants at test concentration was found on the transport of CF across the intestinal membranes. CONCLUSION It maybe possible to improve the absorption of p-gp mediated drugs by co-administration of cremophor EL, labrasol and tween-80 at low concentration, therefore to improve the oral bioavailability of these drugs. KEY WORDS: p- glucoprotein; rhodamine 123; fluorescein sodium; Cremophor EL; Labrasol ; Tween-80 ; diffusion chamber; permeability 60％以上的药物通过口服给药的形式发挥其防病