Purpose

Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters.

Methods

ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

Results

With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively.

Conclusions

The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

中文翻译：

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肾转运蛋白和肾小球滤过介导的急性淋巴细胞白血病的药物清除改变。

目的

在急性淋巴细胞白血病（ALL）中，药物消除改变已有很好的报道。考虑到转运蛋白和肾小球滤过在不同程度上影响药物的分布和可能的副作用，我们评估了ALL对主要肾脏转运蛋白和肾小球滤过介导的药代动力学变化以及肾脏药物转运蛋白表达的影响。

方法

建立所有异种移植模型，分别在NOD / SCID小鼠中静脉注射肾转运蛋白和肾小球滤过基质。使用高效液相色谱-串联质谱（HPLC-MS / MS）测定单剂量后底物的血浆浓度。

结果

随着ALL的发展，肾脏中MDR1，OAT3和OCT2的蛋白质表达分别增加2.62倍，1.70倍和1.45倍，而肾脏中MRP2和MRP4的表达则分别降低30.98％和45.28％。所有组与对照组相比。MDR1介导的地高辛，OAT3介导的速尿和OCT2介导的二甲双胍的清除率分别增加了3.04倍，1.47倍和1.26倍。但是，MRP介导的甲氨蝶呤的清除率降低了39.5％。这些结果与mRNA表达一致。作为肾小球滤过率指标的万古霉素和丁胺卡那霉素的清除率分别在ALL小鼠中增加了2.14倍和1.64倍。

结论

肾脏中肾脏转运蛋白和肾小球滤过的特定改变为ALL的药代动力学变化提供了合理的解释。