蛇床子素及其制剂在Caco-2细胞模型中转运机制的研究

I摘要】目的：研究蛇床子素及其制剂在Caco-2细胞模型中的摄取、转运机制。方法：建立Caco-2细胞单层模型，研究蛇床子素、蛇床予素β-环糊精包合物及其包合物分散片的摄取和跨膜转运，考察其时间、温度、浓度、吸收促进剂和抑制剂对药物摄取及跨膜吸收的影响，并比较原料药与制剂吸收过程的差异。结果：Caco-2细胞对蛇床子素及其制剂溶液的摄取与时间、温度、浓度均呈正相关，p-糖蛋白抑制剂（CyA）与能量抑制剂（NaN3）对摄取无显著性影响，其摄取量的大小依次为分散片〉包合物〉原料药；转运实验中，随浓度和温度的增加，蛇床子素及其制刑的溶液在Caco-2细胞中的转运量均增加，而只r与Rt比值无明显变化，P-糖蛋白抑制剂（CyA）、能量抑制剂（NaN，）、细胞内吞抑制剂．氧化苯砷（oxophenylarsine）7L胞旁路转运促进剂一去氧胆酸钠（sodiumdeoxycholate，SDCh）对蛇床子素的转运无影响，而去氧胆酸钠对包合物和分散片的转运有明显的影响，3种制刑AP—BL方向上的Papp为分散片〉包合物〉原料药。结论：蛇床子素主要以被动扩散的方式被吸收，包合物和分散片中的药物以被动转运为主，少部分以细胞旁路转运途径被细胞吸收；难溶性药物经包合物可促进其吸收，制剂辅料对药物的吸收有一定的促进作用。

Studies on Transport Mechanisms of Osthol and Its Preparations in Caco-2 Cell Model

Objective： To study the mechanisms of uptake and transport of the osthol and its preparations in Caco-2 cell model. Methods：The Caco-2 cell monolayer model was cultivated to investigate the uptake and the transport mech- anisms of the osthol, osthol-β-CD inclusion complex and inclusion complex dispersible tablet across the membranes. The relative factors fbr enchancing the absoption of drug carriers, including time, temperature, drug concentration,the impacts of accelerators and inhibitors were also investigated. The differences between the osthol and its preparations in transport of membranes were explored. Results：The uptake of the osthol and its preparations was positively correlated to time, temperature and drug concentration but not significantly enhanced by the inhibitor of p-glycoprotein （p-gp） and energy（NaN3）.Its intake is： dispersible tablet〉inclusion complex〉osthol. In the transfer experiments, the osthol and its preparations amount transported were increased with loading concentration and temperature. There were no significant differences in the ratios of PBL toPAP at three temperatures. The inhibitors of p-glycoprotein （p-gp）, energy（NaN3） and cells swallowed（oxophenylarsine） and cell bypass transport promoting agents（sodium deoxycholate,SDCh） had no ef- fect on the osthol,but sodium deoxycholate enhanced the drug absorption of inclusion complex and dispersible tablet. Apparent permeability coefficients（P,pp） of basolateral（AP） to apical（BL）： Dispersible tablet〉inclusion complex〉os- thol. Conclusion＇The uptake and absorption of osthol are passive diffusion. The drugs of inclusion complex and dispers- ible tablet are passive transport as the dominant process, a few is absorbed through cell bypass transport pathway. Inclu- sion complex could significantly enhance the drug absorption compared with osthol. Pharmaceutical excipients in the dispersible tablet can promote the drug absorption.