Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes
Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes
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DOI：
10.1093/jac/dkq082
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发表时间：
2010-05-01
影响因子：
5.2
通讯作者：
Khoo, Saye H.
中科院分区：
文献类型：
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作者：
Janneh, Omar;Bray, Patrick G.;Khoo, Saye H.
HIV蛋白酶抑制剂（HPI）的细胞内和血浆浓度在体内变化很大。目前尚不清楚HPIs是否存在浓度依赖性效应，即随着浓度的增加，它们可能会阻断自身的外排（导致“自动提升”）或流入（导致饱和度/细胞内积累减少）。（0-30 μ M）洛匹那韦、沙奎那韦、利托那韦和阿扎那韦分别对[C-14]洛匹那韦、[H-3]沙奎那韦、[H-3]利托那韦和[H-3]阿扎那韦蓄积的影响，在CEMparental、CEMVBL [P-糖蛋白（ABCB 1）过表达]、CEME 1000（MRP 1过表达）和外周血单个核细胞（PBMC）中进行了研究。我们还研究了ABCB 1/ABCG 2（tariquidar）、ABCC（MK 571）和ABCC 1/2（呋塞米）抑制剂单独使用和与HPIs联合使用对细胞蓄积的影响。在所有细胞系中，随着洛匹那韦、沙奎那韦和利托那韦浓度的增加，[C-14]洛匹那韦、[H-3]沙奎那韦和[H-3]利托那韦的细胞蓄积显著增加。塔里克达、MK 571和呋塞米（单独给药和与洛匹那韦、沙奎那韦和利托那韦联合给药）显著增加[C-14]洛匹那韦、[H-3]沙奎那韦和[H-3]利托那韦的蓄积。利托那韦（单独使用或与tariquidar联合使用）可降低PBMC中[H-3]利托那韦的细胞内蓄积。阿扎那韦以浓度依赖性方式降低[H-3]阿扎那韦在所有检测细胞中的蓄积。
The intracellular and plasma concentrations of HIV protease inhibitors (HPIs) vary widely in vivo. It is unclear whether there is a concentration-dependent effect of HPIs such that at increasing concentration they may either block their own efflux (leading to 'autoboosting') or influx (leading to saturability/decreased intracellular accumulation).The effects of various concentrations (0-30 mu M) of lopinavir, saquinavir, ritonavir and atazanavir on the accumulation of [C-14]lopinavir, [H-3]saquinavir, [H-3]ritonavir and [H-3]atazanavir, respectively, were investigated in CEMparental, CEMVBL [P-glycoprotein (ABCB1) overexpressing], CEME1000 (MRP1 overexpressing) and in peripheral blood mononuclear cells (PBMCs). We also investigated the effects of inhibitors of ABCB1/ABCG2 (tariquidar), ABCC (MK571) and ABCC1/2 (frusemide), singly and in combination with HPIs, on cellular accumulation.In all the cell lines, with increasing concentration of lopinavir, saquinavir and ritonavir, there was a significant increase in the cellular accumulation of [C-14]lopinavir, [H-3]saquinavir and [H-3]ritonavir. Tariquidar, MK571 and frusemide (alone and in combination with lopinavir, saquinavir and ritonavir) significantly increased the accumulation of [C-14]lopinavir, [H-3]saquinavir and [H-3]ritonavir. Ritonavir (alone or in combination with tariquidar) decreased the intracellular accumulation of [H-3]ritonavir in PBMCs. Atazanavir decreased the accumulation of [H-3]atazanavir in a concentration-dependent manner in all of the cells tested.There are complex and variable drug-specific rather than class-specific effects of the HPIs on their own accumulation.