Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil
Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil
复制标题
DOI：
10.1111/j.2042-7158.2012.01498.x
复制
发表时间：
2012-08-01
影响因子：
3.3
通讯作者：
Song, Im-Sook
中科院分区：
文献类型：
--
作者：
Choi, Min-Koo;Song, Im-Sook
目的研究伐地那非和西地那非的外排转运特性，并通过P-gp、BCRP和MRP 2等外排转运蛋白比较这两种药物的外排转运动力学。方法我们使用过表达P-gp、BCRP和MRP 2的MDCKII细胞和Caco-2细胞测量了伐地那非和西地那非在1100 μ m浓度范围内的基底-顶端和顶端-基底转运。关键发现：在过表达P-gp、BCRP和MRP 2的MDCKII细胞中，伐地那非的基底-顶端转运率远高于顶端-基底转运率。西地那非显示P-gp和BCRP介导的外排转运，但似乎未通过MRP 2转运蛋白泵出。因此，在1100 μ m的浓度范围内，伐地那非和西地那非在Caco-2细胞中的吸收转运呈线性增加，而这些药物的分泌转运是饱和的，并受到P-gp和BCRP特异性抑制剂的抑制。MK 571是一种代表性的MRP 2抑制剂，可抑制伐地那非的基底-顶端转运，但不抑制西地那非。结论P-gp、BCRP和MRP 2参与伐地那非的分泌转运和线性吸收转运，P-gp和BCRP参与西地那非的分泌转运和线性吸收转运，可能是这些药物在肠道吸收受限的原因。
Objectives We aimed to characterize the efflux transport properties of vardenafil and sildenafil, and to compare the kinetics of these compounds via efflux transporters such as P-gp, BCRP and MRP2. Methods We measured the basal-to-apical and apical-to-basal transport of vardenafil and sildenafil within the concentration range of 1100 mu m using MDCKII cells overexpressing P-gp, BCRP and MRP2, and Caco-2 cells. Key findings Vardenafil had a much greater basal-to-apical than apical-to-basal transport rate in MDCKII cells overexpressing P-gp, BCRP and MRP2. Sildenafil showed P-gp- and BCRP-mediated efflux transport, but did not seem to be pumped out via MRP2 transporters. Consequently, the absorptive transport of vardenafil and sildenafil in Caco-2 cells increased linearly over the concentration range of 1100 mu m, whereas the secretory transport of these drugs was saturable and inhibited by the presence of specific inhibitors of P-gp and BCRP. MK571, a representative MRP2 inhibitor, inhibited the basal-to-apical transport of vardenafil, but not of sildenafil. Conclusion The involvement of P-gp, BCRP and MRP2 for vardenafil and the involvement of P-gp and BCRP for sildenafil in the secretory transport with linear absorptive transport may contribute to the limited intestinal absorption of these drugs.