Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor
Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor
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DOI：
10.1016/j.ijpharm.2007.02.036
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发表时间：
2007-07-18
影响因子：
5.8
通讯作者：
Mitra, Ashim K.
中科院分区：
文献类型：
--
作者：
Agarwal, Sheetal;Pal, Dhananjay;Mitra, Ashim K.
用稳定转染人或小鼠互补DNA(P-gp/mdr1、MRP1、MRP2和Bcrp1)的极化非人(犬)上皮细胞系研究洛比那韦(Lopinavir，LVR)的跨皮转运，并与MDCKII野生型细胞进行比较。这些跨膜蛋白通过减少药物在细胞内的总积聚而导致多药耐药性。洛比那韦的外排是定向的，并可被MDCKII-MRP2细胞中的选择性MRP家族抑制剂MK-571完全抑制。同样，P-gp抑制剂P-gp-4008和GF120918也能抑制MDCKII-MDR1细胞的LVR外流。MDCK-野生型、MDCKII-MDR1、MDCKII-MRP1和MDCKII-MRP2细胞单层在无外排抑制剂的情况下，LVR的外排比分别为1.32、4.91、1.26和2.89。MDCKII-MDR1和MDCKII-MRP2细胞与亲本细胞相比，由于MDR1和MRP2的顶端定向转运，使LVR外流比显著增加。在MK-571和P-gp-4008存在下，MRP2和MDR1细胞株的外排比率接近1，表明MRP2和P-gp的外流完全被它们的选择性抑制剂所抑制。与亲本细胞相比，MDCKII-MRP1细胞的LVR外流没有明显减少，表明LVR不是MRP1的良好底物。跨MDCKII-Bcrp1细胞的转运研究表明，LVR不是由Bcrp1转运的，也不是这种外流蛋白的底物。综上所述，这项研究提供了直接的证据，表明左心室R同时被P-gp和MRP2流出，这可能是导致其口服生物利用度差和限制其在中枢神经系统的渗透的原因之一。(C)2007 Elsevier B.V.保留所有权利。
Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp-4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios of LVR in the absence of any efflux inhibitors in the MDCK-wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp-4008, respectively, indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. (C) 2007 Elsevier B.V. All rights reserved.