Drewe J, Gutmann H, Fricker G, Török M, Beglinger C, Huwyler J
Department of Research and Department of Clinical Pharmacology, University Hospital, Basel, Switzerland.
Biochem Pharmacol. 1999 May 15;57(10):1147-52. doi: 10.1016/s0006-2952(99)00026-x.
The effect of P-glycoprotein inhibition on the 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 IC(50) of 1.13 microM. In addition, the HIV protease inhibitor ritonavir inhibited p-glycoprotein-mediated extrusion of saquinavir with an IC(50) of 0.2 microM, indicating a high affinity of ritonavir for p-glycoprotein. In conclusion, we showed that the 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.
以猪原代脑微血管内皮细胞单层作为体外测试系统，研究了P-糖蛋白抑制对1型人类免疫缺陷病毒蛋白酶抑制剂沙奎那韦进入脑微血管内皮细胞摄取的影响。经聚合酶链反应和蛋白质印迹分析证实，该系统功能性表达I类P-糖蛋白（pgp1A）。未检测到P-糖蛋白异构体pgp1B或pgp1D。沙奎那韦进入内皮细胞的摄取可描述为摄取扩散项和相反方向的饱和外排过程的结果。SDZ PSC 833可使沙奎那韦进入培养的脑内皮细胞的净摄取量以剂量依赖方式显著增加高达2倍，IC(50)为1.13 microM。此外，HIV蛋白酶抑制剂利托那韦抑制P-糖蛋白介导的沙奎那韦外排，IC(50)为0.2 microM，表明利托那韦对P-糖蛋白具有高亲和力。总之，我们表明HIV蛋白酶抑制剂利托那韦是比多药耐药（MDR）逆转剂SDZ PSC 833更有效的P-糖蛋白抑制剂。在联合治疗方案中加入这种药物可能会极大地促进HIV蛋白酶抑制剂的脑摄取，这在患有艾滋病痴呆综合征的患者中尤为重要。
