P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines.
P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines.
复制标题
DOI：
10.1248/bpb.32.1588
复制
发表时间：
2009-09
影响因子：
2
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Fujimoto H;Higuchi M;Watanabe H;Koh Y;Ghosh AK;Mitsuya H;Tanoue N;Hamada A;Saito H
达芦那韦（DRV）是一种非肽类蛋白酶抑制剂（PI），获批用于治疗人类免疫缺陷病毒（HIV）感染。DRV对其他可用PI耐药的HIV毒株显示出强效活性。与利托那韦（RTV）联合给药可提高DRV的口服生物利用度。RTV抑制细胞色素P450被认为是提高DRV生物利用度的一种机制。然而，这些药物与肠道转运蛋白的相互作用尚未阐明。本研究旨在探讨P-糖蛋白在人肠Caco-2单层和ABCB 1多药耐药1（MDR 1）基因转染的肾LLC-PK 1（L-MDR 1）细胞系中跨细胞DRV转运中的参与。DRV在Caco-2细胞单层中的跨上皮转运在基底-顶端方向上是相反方向的2倍。RTV对DRV在Caco-2细胞中的外排转运有明显的抑制作用。P-糖蛋白抑制剂环孢菌素A和维拉帕米以及多药耐药相关蛋白（MRP/ABCC）抑制剂丙磺舒和MK 571可增强DRV的顶面至底面转运。使用L-MDR 1细胞系，从基底到顶端的DRV转运远大于相反方向。此外，环孢菌素A显着抑制基底到顶端的DRV运输。RTV显著增加了DRV在L-MDR 1细胞中的顶向基底转运，但减少了相反方向的转运。DRV抑制L-MDR 1细胞中P-糖蛋白介导的钙黄绿素-乙酰氧基甲酯外排，抑制效力为121 µM。这些发现表明DRV是P-糖蛋白和MRP（最可能是MRP 2）的底物。RTV似乎抑制P-糖蛋白，从而增强DRV的吸收转运。
Darunavir (DRV) is a nonpeptidic protease inhibitor (PI) approved for the treatment of human immunodeficiency virus (HIV) infection. DRV displays potent activity against HIV strains resistant to other available PIs. Coadministration with ritonavir (RTV) improves the oral bioavailability of DRV. Inhibition of cytochrome P450 by RTV has been proposed as a mechanism for enhanced DRV bioavailability. However, interaction of these drugs with intestinal transporters has not been elucidated. This study was performed to explore the involvement of P-glycoprotein in transcellular DRV transport in monolayers of human intestinal Caco-2 and in ABCB1 multidrug resistance 1, (MDR1) gene-transfected renal LLC-PK1 (L-MDR1) cell lines. Transepithelial transport of DRV in Caco-2 cell monolayers was 2-fold greater in the basal-to-apical direction compared to that in the opposite direction. RTV had a significant inhibitory effect on the efflux transport of DRV in Caco-2 cells. The apical- to-basal DRV transport was enhanced by P-glycoprotein inhibitors, cyclosporin A and verapamil, as well as multidrug resistance-related protein (MRP/ABCC) inhibitors, probenecid and MK571. Using the L-MDR1 cell line, basal-to-apical DRV transport was much greater than in the opposite direction. Furthermore, cyclosporin A markedly inhibited the basal-to-apical DRV transport. RTV significantly increased the apical-to-basal transport of DRV in L-MDR1 cells, but reduced transport in the opposite direction. DRV inhibited P-glycoprotein-mediated efflux of calcein-acetoxymethyl ester in L-MDR1 cells with the inhibitory potency of 121 µM. These findings suggest that DRV is a substrate of P-glycoprotein and MRP, most likely MRP2. RTV appeared to inhibit P-glycoprotein, thereby enhancing the absorptive transport of DRV.
登录
查看更多内容
影响因子：
3.8
作者：
Boffito, Marta;Winston, Alan;Gazzard, Brian
通讯作者：
Gazzard, Brian
影响因子：
3.9
作者：
Anderson, BD;May, MJ;Leggas, M
通讯作者：
Leggas, M
影响因子：
3.8
作者：
Huisman, MT;Smit, JW;Schinkel, AH
通讯作者：
Schinkel, AH
影响因子：
3.9
作者：
Sai, Yoshimichi;Kaneko, Yosuke;Tsuji, Akira
通讯作者：
Tsuji, Akira
影响因子：
4.8
作者：
Koh, Yasuhiro;Matsumi, Shintaro;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki