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Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration

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Abstract

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.

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Abbreviations

ABC:

ATP-binding cassette

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BCRP:

Breast cancer resistance protein

CL:

Clearance

GFR:

Glomerular filtration ratio

MDR:

Multidrug resistance

MRPs:

Multidrug resistance proteins

OATs:

Organic anion transporters

OCTs:

Organic cation transporters

PK:

Pharmacokinetics

SLC:

Solute carrier

TRM:

Treatment-related mortality

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2017ZX09304029-002), National Science Foundation of China (81703603), Young Taishan Scholars Program of Shandong Province, Qilu Young Scholars Program of Shandong University.

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Author notes

  1. Yi Zheng and Wei Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Yue Zhou, Bin Du, Min Kan, Bo-Hao Tang, Ai-Qing Nie, Guo-Xiang Hao, Yi Zheng & Wei Zhao

  2. Institute of Biochemical and Biotechnological Drug, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Shang Chen

  3. Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China

    Pan-Pan Ye

  4. Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

    Pan-Pan Ye, Hai-Yan Shi & Wei Zhao

  5. Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Xiu-Li Guo

  6. Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Qiu-Ju Han

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  1. Yue Zhou
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Correspondence to Yi Zheng or Wei Zhao.

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Zhou, Y., Du, B., Kan, M. et al. Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration. Pharm Res 37, 158 (2020). https://doi.org/10.1007/s11095-020-02896-8

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