Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1
Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1
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DOI：
10.3109/00498250903509375
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发表时间：
2010-03-01
期刊：
影响因子：
1.8
通讯作者：
Augustijns, P.
中科院分区：
文献类型：
--
作者：
Annaert, P.;Ye, Z. W.;Augustijns, P.
1.检测了人类免疫缺陷病毒(HIV)蛋白水解酶抑制剂(PI)对表达有机阴离子转运多肽(OATP)-1B1和-1B3的中国仓鼠卵巢(CHO)细胞中胆盐类似物胆碱-甘氨酰亚胺-荧光素(CGamF)积聚的影响。此外，由于在Caco-2单层中没有观察到CGamF的积累，因此使用已建立的OATP底物3-硫酸酯雌酮(E3S)在Caco-2单层中进行了相互作用研究，已知仅表达OATP2B1亚型。CGamF是OATP1B亚家族的良好底物，在OATP1B1和OATP1B3细胞中，CGamF的净累积清除值分别为7.8mU L min(-1)mg(-1)蛋白和142mU OATP1B3蛋白。反映HIV PI抑制CGAMF积聚的K(I)值在表达OATP1B1和OATP1B3的细胞中具有很好的相关性。洛比那韦对OATP1B介导的CGamF积累的抑制作用最强(K(I)=0.5~1.4mU M)，而阿扎那韦、达鲁那韦、利托那韦和萨奎那韦(K(I)=1.4~3.3mU M之间)。对OATP2B1介导的E3S积聚的抑制谱不同，只有吲哚那韦、萨奎那韦和利托那韦表现出显著的效果。综上所述，OATP1B3可能是介导钠非依赖性CGamF在人体肝脏蓄积的主要转运机制，CGamF可作为体外药物相互作用研究的探针底物。洛匹那韦对OATP1B1的显著抑制作用可能解释了洛匹那韦与非索非那定等OATP1B底物之间的一些临床相关药物相互作用。
1. The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers.2. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 mu l min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 mu M) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 mu M).3. Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects.4. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.