替米沙坦在Caco-2细胞模型中的体外转运研究

 目的研究替米沙坦(telmisartan,TMS)在Caco-2细胞中的跨膜转运特征。方法采用体外培养的人小肠上皮细胞Caco-2模型对TMS的跨膜转运进行研究。考察了浓度、pH、P-糖蛋白(P-glyprotein,P-gp)抑制剂对TMS跨膜转运的影响。结果TMS在Caco-2细胞中的转运存在外排作用,并且外排作用随着浓度的增加趋于饱和;另外TMS的吸收转运随pH值的增加而减少。加入P-糖蛋白抑制剂环孢素A和胺碘酮后,P_ratio从3.5分别下降到1.2和0.9,加入前后有极显著性差异(P<0.01)。结论P-gp参与了TMS的跨膜转运,从而从吸收机制上初步解释了P-gp的外排作用可能是TMS生物利用度低,个体差异大的原因。

Transport Characteristics of Telmisartan in Human Intestinal Cell Line Caco-2

OBJECTIVE To study the transport characteristics of telmisartan in vitro. METHODS A human intestinal epithelial cell Caco-2 model in vitro was applied to study the transport characteristics of telmisartan. The effects of concentration, pH and P-glycoprotein(P-gp) inhibitors on the transport of telmisartan were investigated. RESULTS In the Caco-2 cells, the absorptive transport of TMS was pH dependent and the transport was enhanced at weakly acidic pH on the apical side. The comparison of apical to basolateral(AP-BL)and basolateral to apical(BL-AP)transports showed that efflux effects limited the oral absorption of TMS. In the presence of amioderone(10 μmol·L^-1) and cyclosporin(10 μmol·L^-1), potent inhibitors of P-gp, the P_ratio decreased from 3.5 to 0.9 and 1.2,respectively(P<0.01). CONCLUSION The polarized efflux of TMS in Caco-2 cell is probably due to the presence of P-gp. The results initially explain the reasons for low and variable bioavailability of TMS, and provide a guidance for the rational treatment of hypertension.