Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration
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RESEARCH PAPER
Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration Yue Zhou 1 & Bin Du 1 & Min Kan 1 & Shang Chen 2 & Bo-Hao Tang 1 & Ai-Qing Nie 1 & Pan-Pan Ye 3,4 & Hai-Yan Shi 4 & Guo-Xiang Hao 1 & Xiu-Li Guo 5 & Qiu-Ju Han 6 & Yi Zheng 1 & Wei Zhao 1,4
Received: 26 March 2020 / Accepted: 27 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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 chromatographytandem mass spectrometry (HPLC-MS/MS). Results With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70fold, 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, OAT3mediated 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.
KEY WORDS acute lymphoblastic leukemia . clearance . glomerular filtration . renal transporters
ABBREVIATIONS ABC ALL AML BCRP CL GFR
ATP-binding cassette Acute lymphoblastic leukemia Acute myeloid leukemia Breast cancer resistance protein Clearance Glomerular filtration ratio
Yi Zheng and Wei Zhao contributed equally to this work. * Yue Zhou
Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
* Yi Zheng [email protected]
3
Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
* Wei Zhao [email protected]
4
Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
5
Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
6
Institute of Immunopharmaceutical Sciences, Sc
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