HIV protease inhibitor ritonavir:: A more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833
HIV protease inhibitor ritonavir:: A more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833
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DOI：
10.1016/s0006-2952(99)00026-x
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发表时间：
1999-05-15
影响因子：
5.8
通讯作者：
Huwyler, J
中科院分区：
文献类型：
--
作者：
Drewe, J;Gutmann, H;Huwyler, J
以猪原代脑毛细血管内皮细胞单层为实验系统，研究了P-糖蛋白抑制对HIV 1型蛋白酶抑制剂沙奎那韦摄取脑毛细血管内皮细胞的影响。经聚合酶链式反应和Western印迹分析证实，该系统能表达I类P-糖蛋白(Pgp1A)。未检测到P-糖蛋白异构体pgp1B或pgp1D。沙奎那韦对内皮细胞的摄取可以描述为扩散摄取和相反方向的饱和挤出过程的结果。SDZ PSC 833可剂量依赖性地使培养的脑血管内皮细胞对沙奎那韦的净摄取量增加2倍，IC50为1.13mM。此外，HIV蛋白水解酶抑制剂利托那韦也能显著提高脑血管内皮细胞对沙奎那韦的净摄取量。P-糖蛋白介导的沙奎那韦的IC50为0.2um M，表明利托那韦对F-糖蛋白有很高的亲和力。综上所述，我们发现HIV蛋白酶抑制剂利托那韦是一种比多药耐药(MDR)逆转剂SDZ PSC 833更有效的P-糖蛋白抑制剂。将这种药物纳入联合治疗方案可能会极大地促进大脑对艾滋病毒蛋白水解酶抑制剂的吸收，这对患有艾滋病痴呆综合征的患者尤其重要。(C)1999年爱思唯尔科学公司。
The effect of P-glycoprotein inhibition on thr uptake of the HIV type 1 protease inhibitor saquinavir into brain capillary endothelial cells was studied using porcine primary brain capillary endothelial cell monolayers as an in vitro test system. As confirmed by polymerase chain reaction and Western blot analysis, this system functionally expressed class I P-glycoprotein (pgp1A). P-Glycoprotein isoforms pgp1B or pgp1D could not be detected. The uptake of saquinavir into endothelial cells could be described as the result of a diffusional term of uptake and an oppositely directed saturable extrusion process. Net uptake of saquinavir into cultured brain endothelial cells could be increased significantly up to 2-fold by SDZ PSC 833 in a dose-dependent manner, with an IC50 of 1.13 mu M. In addition, the HIV protease inhibitor ritonavir inhibitor. p-glycoprotein-mediated extrusion of saquinavir with an IC50 of 0.2 mu M, indicating a high affinity of ritonavir for F-glycoprotein. In conclusion, we showed that thr HIV protease inhibitor ritonavir is a more potent inhibitor of P-glycoprotein than the multidrug resistance (MDR)-reversing agent SDZ PSC 833. The inclusion of this drug in combination regimens may greatly facilitate brain uptake of HIV protease inhibitors, which is especially important in patients suffering from AIDS dementia complex. (C) 1999 Elsevier Science Inc.