Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine
Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine
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DOI：
10.1124/dmd.106.014274
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发表时间：
2007-07-01
影响因子：
3.9
通讯作者：
Elmquist, William F.
中科院分区：
文献类型：
--
作者：
Pan, Guoyu;Giri, Nagdeep;Elmquist, William F.
阿巴卡韦（ABC）和齐多夫定（AZT）在病毒库中的生物利用度和靶向分布可能受到外排转运体的影响。本研究的目的是利用Bcrp1转染的Madin- Darby犬肾II细胞模型，表征这些核苷类逆转录酶抑制剂与Abcg2/Bcrp1转运体的相互作用，Abcg2/Bcrp1转运体是人类乳腺癌抵抗蛋白（BCRP）的小鼠同源物。与野生型细胞相比，转染Bcrp1的细胞内ABC和AZT的积累分别显著减少了约90%和70%。与野生型定向通量相比，ABC和AZT均显著增加了Bcrp1细胞的基底外侧到根尖（B-to-A）转运，减少了根尖到基底外侧（A-to-B）转运。在bcrp1转染的细胞中，ABC的外排比（B-to-A与A-to-B之比）为22，AZT为11。N-（4-[2-（1,2,3,4四氢- 6,7-二甲氧基- 2-异喹啉基）乙基]-苯基）- 9,10-二氢- 5-甲氧基- 9-氧-4-吖啶羧酰胺（GF120918）抑制了两种细胞变体之间的这种积累差异，ABC的EC50为1.32 +/- 0.3 μ M， AZT的EC50为0.31 +/- 0.1 μ M。Ko143（3（6-异丁基- 9-甲氧基- 1,4-二氧基- 1,2,3,4,6,7,12,12a-八氢吡嗪基[1',2':1,6]吡啶[3,4- b]吲哚- 3-基）-丙酸叔丁基酯）对ABC的EC50为121 +/- 5 nM，对AZT的EC50为19.2 +/- 1.5 nM（希尔系数与3- 6相似）。Probenecid是一种已知影响AZT生物分布的有机阴离子抑制剂，在Bcrp1模型中对细胞积累没有影响。这些研究表征了Bcrp1介导的ABC和AZT的转运，并表明典型的BCRP抑制剂GF120918和Ko143可以抑制Bcrp1介导的这些重要抗逆转录病毒化合物的转运。BCRP在关键屏障（如肠肠细胞、脑毛细血管内皮和靶淋巴细胞）的功能表达可能影响这些药物的生物利用度和靶向递送。
The bioavailability and targeted distribution of abacavir ( ABC) and zidovudine ( AZT) to viral reservoirs may be influenced by efflux transporters. The purpose of this study was to characterize the interaction of these nucleoside reverse transcriptase inhibitors with the Abcg2/Bcrp1 transporter, the murine homolog of human breast cancer resistance protein ( BCRP), using a Bcrp1- transfected Madin- Darby canine kidney II cell model. Intracellular accumulation of ABC and AZT was significantly reduced by similar to 90% and similar to 70%, respectively, in Bcrp1- transfected cells compared with the wild- type cells. Both ABC and AZT showed significantly increased basolateral-to-apical ( B-to-A) and decreased apical-to-basolateral (A-to-B) transport in Bcrp1 cells compared with wild- type directional flux. The efflux ratio ( ratio of B-to-A to A-to-B) in Bcrp1-transfected cells was 22 for ABC and 11 for AZT. N-( 4-[ 2-( 1,2,3,4tetrahydro- 6,7- dimethoxy- 2- isoquinolinyl) ethyl]- phenyl)- 9,10-dihydro- 5- methoxy- 9-oxo-4-acridine carboxamide ( GF120918) inhibited this difference in accumulation between the two cell variants with an EC50 of 1.32 +/- 0.3 mu M for ABC and 0.31 +/- 0.1 mu M for AZT. Potent and highly cooperative inhibition by Ko143 ( 3( 6- isobutyl- 9- methoxy- 1,4- dioxo- 1,2,3,4,6,7,12,12a- octahydropyrazino[ 1', 2': 1,6] pyrido[ 3,4- b] indol- 3- yl)- propionic acid tert- butyl ester) was observed with an EC50 of 121 +/- 5 nM for ABC and 19.2 +/- 1.5 nM for AZT ( Hill coefficient similar to 3 - 6). Probenecid, an organic anion inhibitor known to influence AZT biodistribution, had no effect on cellular accumulation in the Bcrp1 model. These studies characterize the Bcrp1- mediated transport of ABC and AZT and show that prototypical BCRP inhibitors GF120918 and Ko143 can inhibit the Bcrp1- mediated transport of these important antiretroviral compounds. The functional expression of BCRP at critical barriers, such as the intestinal enterocytes, brain capillary endothelium, and target lymphocytes, could influence the bioavailability and targeted delivery of these drugs to sanctuary sites.